Contract
DELIBERAZIONE N. 140 DEL 08/02/2023 | |
OGGETTO: PRESA D'ATTO STIPULA CONVENZIONE ED ACCETTAZIONE FINANZIA- MENTO DI EURO 1.000.000,00 DISPOSTO DAL MINISTERO DELLA SALUTE IN FAVORE DI IFO IRCCS IRE PER IL PROGETTO CODICE PNRR-MAD-2022-12375670 "ADDRES- SING LIVER FIBROSIS PREVENTION AND TREATMENT:AN UNBIASED QUERY ON THE HEPATIC MICROENVIRONMENT WITH A PERSPECTIVE TARGETING OF THE PRO- FIBROTIC KINASE HIPK2" RESP. DOTT.SSA XXXXXX XXXXX CUP H53C22001160001 | |
Esercizi/o 2022/2024 - 401030201 | STRUTTURA PROPONENTE |
Centri/o di costo - | UOSD Servizio Amministrativo Ricerca |
- Importo presente Atto: € x0.000.000,00 | Il Dirigente Responsabile |
- Importo esercizio corrente: € x0.000.000,00 | Xxxxxxx Xxxxxx |
Budget | |
- Assegnato: € - | |
- Utilizzato: € - | |
- Residuo: € - | |
Autorizzazione n°: - | |
Servizio Risorse Economiche: Xxxxxxxxx Xxxxxx Be- nedetto | Responsabile del Procedimento |
Xxxxxxx Xxxxxx | |
L’Estensore | |
Lucia D'Auria | |
Proposta n° DL-111-2023 | |
PARERE DEL DIRETTORE SANITARIO | PARERE DEL DIRETTORE AMMINISTRATIVO |
Positivo | Positivo |
Data 08/02/2023 | Data 08/02/2023 |
IL DIRETTORE SANITARIO Xxxxxx Xxxxx | IL DIRETTORE AMMINISTRATIVO Xxxxx Xxxxxxxxx |
Xxxxxx del Direttore Scientifico IRE Xxxxxxx Xxxxxxxxx data 06/02/2023 Positivo Parere del Direttore Scientifico ISG Xxxx Xxxxxxx data 06/02/2023 Positivo | |
La presente deliberazione si compone di n° 8 pagine e dei seguenti allegati che ne formano parte integrante e sostanziale: All.1 Convenzione | |
Il Dirigente della UOSD Servizio Amministrativo Ricerca
Visto il decreto legislativo 30.12.1992, n. 502 e successive modificazioni ed integrazioni. Visto il decreto legislativo 16.10.2003, n. 288.
Vista la legge regionale 23.01.2006, n. 2.
Visto l’Atto Aziendale adottato con deliberazione n. 153 del 19.02.2019 e approvato dalla Regione Lazio con DCA n. U00248 del 2.07.2019, modificato e integrato con deliberazioni n. 1254 del 02.12.2020, n. 46 del 21/01/2021 e n. 380 del 25.03.2021, approvate dalla Direzione Sa- lute ed Integrazione Sociosanitaria della Regione Lazio, con Determinazione n. G03488 del 30.03.2021.
Visto il Decreto del Presidente della Regione Lazio n. T00200 del 29/10/2021 avente ad oggetto: “Nomina del Direttore Generale dell’IRCCS IFO-Istituti Fisioterapici Ospitalieri.
Vista la deliberazione n.1123 del 2/11/2021 di insediamento ed assunzione in carica del Direttore Generale degli Istituti Fisioterapici Ospitalieri di Roma Dott. ssa Xxxxxx Xxxxxxxx.
Viste le deliberazioni n. 212 del 16/03/2022 e n. 154 del 28/02/2022 con le quali sono stati nomi- nati rispettivamente la Dott. ssa Xxxxx Xxxxxxxxx quale Direttore Amministrativo ed il Xxxx. Xxxxxx Xxxxx quale Direttore Sanitario degli Istituti Fisioterapici Ospitalieri.
Visto il D.M. del Ministero della Salute del 8 maggio 2020 di conferma del riconoscimen to del ca- rattere scientifico dell’IRCCS di diritto pubblico a Istituti Fisioterapici Ospitalieri (IFO) re- lativamente alla disciplina di “oncologia” per l’Istituto Nazionale Tumori Regina Xxxxx (IRE) e alla disciplina di “dermatologia” per l’Istituto San Gallicano;
Premesso che l’art. 7 del decreto legislativo 16 ottobre 2003 n. 288, contempla le diverse tipologie di rica- vi degli IRCCS;
che l’art. 8 del D.Lgs. n. 288/2003 prevede la possibilità per gli IRCCS di stipulare accordi e convenzioni, costituire e/o partecipare a consorzi e attuare misure di collegamento e sinergia con altre strutture di ricerca e assistenza sanitaria, pubbliche e private, nonché con le Universi- tà, per la realizzazione di comuni progetti di ricerca;
che il vigente Regolamento di Organizzazione e Funzionamento degli IFO definisce, fra l’altro, come missione degli IRCCS la cooperazione con altri enti pubblici di ricerca e con altre organizzazioni che operano negli specifici campi, in una logica di completamento di ruoli e di continuità assistenziale;
che con deliberazione n. 146 del 24/02/2022 il Direttore Generale degli IRCCS IFO, in ordine alla stipula degli accordi di riservatezza con i partner degli Istituti, degli MTA e degli MTDA relativi alle sperimentazioni cliniche, agli studi osservazionali, ai brevetti e comunque ai pro- getti di ricerca ha esteso delega ai Direttori Scientifici IRE e ISG per le attività afferenti i ri - spettivi Istituti.
Rilevato il I° avviso pubblico per la presentazione e selezione di progetti di ricerca da finanziare nell’ambito del PNRR, pubblicato sul sito web del Ministero della salute il 20 aprile 2022 e sulla gazzetta ufficiale della Repubblica italiana;
il decreto direttoriale n. 27 del 2 novembre 2022, registrato con Visto n. 1054 dall’Uffi- cio centrale di bilancio in data 18 novembre 2022, con il quale è stata approvata la gra- duatoria dei progetti di ricerca PNRR ed i relativi Principal Investigator;
Considerato che con il messaggio trasmesso per il tramite della piattaforma WorkFlow della ricerca in data 13 dicembre 2022 è stato comunicato che la valutazione della proposta progettuale ha avuto esito positivo e che, pertanto, la stessa è stata ammessa a finanziamento;
che al progetto con codice PNRR-MAD-2022-12375670 dal titolo Addressing liver fi- brosis prevention and treatment: anunbiased query on the hepatic microenvironment with a perspective targeting of the pro-fibrotic kinase HIPK2,
Destinatario Istituzionale - Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Elena – di cui il la dott.ssa Xxxxxx Xxxxx è Principal Investigator e utilmente collo- cato nella specifica graduatoria, è stato attribuito un finanziamento complessivo di 1.000.000,00 €, di cui euro 400.000,00 (quattrocentomila/00) in favore di IFO IRCCS IRE ;
Visto che tra il Ministero della Salute e l’IFO IRCCS IRE è stata stipulata la Convenzione fa- cente riferimento al progetto PNRR-MAD-2022-12375670 (Allegato 1), ai fini dello svolgimento del progetto di ricerca e per disciplinare i rapporti tra le parti e che, la stessa allegata in copia conforme all’originale, rappresenta parte integrante e sostanziale del presente atto;
Rilevato che gli Istituti Fisioterapici Ospitalieri – Istituto Nazionale Tumori Xxxxxx Xxxxx hanno presentato il progetto, oggetto del presente atto, in qualità di Destinatario Istituzionale e tramite il Principal Investigator, Dr.ssa Xxxxxx Xxxxx, svolgerà lo stesso secondo quanto ri- portato nel piano esecutivo approvato dal Ministero, agli atti della scrivente;
che la convenzione ha la durata di 24 mesi prorogabile eventualmente di ulteriori 6 mesi come previsto dall’ articolo 11.
che l’attività di ricerca, da svolgersi nell’arco temporale della vigenza della convenzione, deve avere inizio improrogabilmente entro e non oltre il 20 maggio 2023, comunicando la data effettiva di avvio con nota sottoscritta digitalmente dal proprio rappresentante legale e dal Principal investigator della ricerca che deve essere trasmessa almeno 30 giorni prima dell’inizio effettivo, correlata di documentazione idonea;
Atteso che le procedure di erogazione dei fondi su richiesta del Soggetto attuatore/beneficiario a titolo di anticipazione e a titolo di rimborso all’Unità di missione del Ministero della salu- te seguono le specifiche modalità in conformità con quanto indicato nell’Avviso e di se- guito riportate:
- massimo 40% al momento della comunicazione, da parte del Soggetto beneficiario, dell’inizio dell’attività di ricerca, a titolo di anticipazione.
- quota a rimborso per un ulteriore per massimo un complessivo pari all’80% dopo l’invio, al 12° mese dall’inizio delle attività progettuali, da parte del Soggetto at- tuatore/beneficiario della relazione scientifica intermedia e dopo la sua approva- zione, sulla base della presentazione delle richieste di pagamento a titolo di rim- borso per le spese effettivamente sostenute dal Soggetto beneficiario.
- quota a rimborso residuale a saldo, a conclusione della ricerca, dopo l’invio da parte del Soggetto attuatore/beneficiario della relazione scientifica finale e della rendi- contazione economica, sulla base della presentazione della richiesta di paga- mento finale attestante la conclusione del progetto.
Visto
che alla realizzazione del progetto parteciperanno gli IFO IRCCS IRE e altre n° 3 Unità Operative: Università Xxxxxxxx II Napoli, Istituto Nazionale Tumori IRCCS Fondazione Xxxxxxx e Verona University Hospital Trust, per un finanziamento complessivo di 1.000.000,00 €, la cui distribuzione del finanziamento è la se- guente:
Costs | UO1 IFO | OU2 Università Fe- derico II Napoli | UO3 IRCCS Xxxxxxx Xxxxxx | UO4 Verona Uni- versity Hospital Trust | Totale | % |
1 Staff Salary | not permitted | not permitted | not permitted | not permitted | - € | 0,00% |
2 Researchers' Contracts | 50.000,00 € | 160.000,00 € | 60.000,00 € | 40.000,00 € | 310.000,00 € | 31,00% |
3a.1 Equipment (Leasing - Rent) | - € | 56.000,00 € | - € | - € | 56.000,00 € | 5,60% |
3a.2 Equipment (buying) | - € | - € | - € | - € | - € | 0,00% |
3b Supplies | 203.000,00 € | 140.000,00 € | 24.000,00 € | 43.000,00 € | 410.000,00 € | 41,00% |
3c Model Costs | 15.000,00 € | - € | - € | - € | 15.000,00 € | 1,50% |
4 Subcontracts | - € | - € | - € | - € | - € | 0,00% |
5 Patient Costs | - € | - € | - € | - € | - € | 0,00% |
6 IT Services and Data Bases | 30.000,00 € | - € | 4.000,00 € | 5.000,00 € | 39.000,00 € | 3,90% |
7 Travels | 12.000,00 € | 6.000,00 € | 1.000,00 € | 1.000,00 € | 20.000,00 € | 2,00% |
8 Publication Costs | 20.000,00 € | 6.000,00 € | 2.000,00 € | 2.500,00 € | 30.500,00 € | 3,05% |
9 Dissemination | 12.000,00 € | 4.000,00 € | 2.000,00 € | 1.500,00 € | 19.500,00 € | 1,95% |
10 Overheads | 28.000,00 € | 28.000,00 € | 7.000,00 € | 7.000,00 € | 70.000,00 € | 7,00% |
11 Coordination Costs | 30.000,00 € | not permitted | not permitted | not permitted | 30.000,00 € | 3,00% |
Totale | 400.000,00 € | 400.000,00 € | 100.000,00 € | 100.000,00 € | 1.000.000,0 0 € | 100% |
Visto che il codice CUP del progetto, oggetto del presente atto, è H53C22001160001;
Preso atto della nota folium n. 16837 del 15 dicembre 2022 con cui la Direzione Scientifica IRE richiedeva di provvedere alla relativa procedura deliberativa della convenzio- ne allegata;
Xxxxxxxx opportuno prendere atto della Convenzione relativa al progetto con codice PNRR-MAD- 2022-12375670 dal titolo Addressing liver fibrosis prevention and treatment: anunbiased query on the hepatic microenvironment with a perspective targe- ting of the pro-fibrotic kinase HIPK2 Destinatario Istituzionale - Istituti Fisiote- rapici Ospitalieri - Istituto Nazionale Tumori Regina Xxxxx – di cui la dott.ssa Xxxxxx Xxxxx è Principal Investigator e unitamente accettare il finanziamento complessivo di euro 1.000.000,00 €, (unmilione/00) di cui euro 400.000,00 (quattrocentomila/00) in favore di IFO IRCCS IRE;
Attestato che il presente provvedimento, a seguito dell’istruttoria effettuata, nella forma e nella sostanza è totalmente legittimo e utile per il servizio pubblico, ai sensi dell’art. 1 della legge 20 del 14/01/1994 e successive modifiche, nonché alla stregua dei criteri di economicità e di efficacia di cui all’art. 1, primo comma, della legge 241 del 7/08/1990, come modificata dalla legge 15 del 11/02/2005;
Propone
Per i motivi di cui in narrativa che si intendono integralmente confermati di:
• prendere atto della Convenzione relativa al progetto con codice PNRR-MAD-2022-12375670 dal titolo Addressing liver fibrosis prevention and treatment: anunbiased query on the hepatic mi- croenvironment with a perspective targeting of the pro-fibrotic kinase HIPK2 Destinatario Istituzionale
- Istituti Fisioterapici Ospitalieri - Istituto Nazionale Tumori Regina Xxxxx – di cui la dott.ssa Xxxxxx Xxxxx è Principal Investigator;
• accettare il finanziamento complessivo di euro 1.000.000,00 €, (unmilione/00) di cui euro 400.000,00 (quattrocentomila/00) in favore di IFO IRCCS IRE ;
• dare mandato al Servizio Risorse Economiche di iscrivere al piano dei conti n. 401030201 la somma di euro 1.000.000,00 € (unmilione/00) di cui euro 400.000,00 (quattrocentomila/00) in favore di IFO IRCCS IRE).
La UOSD Servizio Amministrativo per la Ricerca curerà tutti gli adempimenti per l’esecuzione del- la presente deliberazione.
Il Dirigente della UOSD Servizio Amministrativo Ricerca Xxxxxxx Xxxxxx
Il Direttore Generale
Visto il Decreto Legislativo 30.12.1992, n. 502 e successive modificazioni ed integrazioni; Vista la Legge Regionale 23.01.2006, n. 2;
Visto l’Atto Aziendale adottato con deliberazione n. 153 del 19.02.2019 e approvato dalla Regione Lazio con DCA n. U00248 del 2.07.2019, modificato e integrato con delibe- razioni n. 1254 del 02.12.2020, n. 46 del 21/01/2021 e n. 380 del 25.03.2021, appro- vate dalla Direzione Salute ed Integrazione Sociosanitaria della Regione Lazio, con Determinazione n. G03488 del 30.03.2021;
In virtù dei poteri conferitigli con Decreto del Presidente della Regione Lazio n. T00200 del 29.10.2021.
Preso atto che il Dirigente proponente il presente provvedimento, sottoscrivendolo, attesta che lo stesso a seguito dell’istruttoria effettuata, nella forma e nella sostanza è totalmente legittimo e utile per il servizio pubblico, ai sensi dell’art. 1 della legge 20/94 e s.m.i., nonché alla stregua dei criteri di economicità e di efficacia di cui all’art. 1, primo comma, della legge 241/90, come modificata dalla legge 15/2005.
Visto il parere favorevole del Direttore Amministrativo e del Direttore Sanitario Aziendale; ritenuto di dover procedere;
Delibera
di approvare la proposta così formulata concernente “PRESA D'ATTO STIPULA CONVENZIONE ED AC- CETTAZIONE FINANZIAMENTO DI EURO 1.000.000,00 DISPOSTO DAL MINISTERO DELLA SALUTE IN FAVO- RE DI IFO IRCCS IRE PER IL PROGETTO CODICE PNRR-MAD-2022-12375670 "ADDRESSING LIVER FIBROSIS PREVENTION AND TREATMENT:AN UNBIASED QUERY ON THE HEPATIC MICROENVIRONMENT WITH A PERSPECTIVE TARGETING OF THE PRO-FIBROTIC KINASE HIPK2" RESP. DOTT.SSA XXXXXX XXXXX CUP
H53C22001160001” e di renderla disposta.
Il Direttore Generale Dr.ssa Xxxxxx Xxxxxxxx
Documento firmato digitalmente ai sensi del D.Lgs 82/2005 s.m.i. e norme collegate
PIANO NAZ IONALE DI RIPRESA E RESILIENZ A (PNRR) MISSIONE 6 - COMPONENTE 2
INVESTIMENTO 2.1 VALORIZ Z AZ IONE E POTENZ IAMENTO DELLA RICERCA
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Pr e m e s s o c h e
VISTA l a l e g g e 7 a g o s t o 1990, n . 241 “ Nu o v e n o r m e i n m a t e r i a d i d i r i t t o d i a c c e s s o a i d o c u m e n t i a m m i n i s t r a t i v i ” e s .m VISTA l a l e g g e 14 g e n n a i o 1994 n . 20 “ Di s p o s i z i o n i i n m a t e r i a d e i Co n t i ” e s .m .i .;
VISTO l ’ a r t i c o l o 12 b i s , c o m m a 3, d e l d e c r e t o l e g i s l a t i v o 3 VISTO i l d e c r e t o d e l Pr e s i d e n t e d e l Co n s i g l i o d e i Mi n i s t d i o r g a n i z z a z i o n e d e l Mi n i s t e r o d e l l a s a l u t e e , i n p a r VISTO i l d e c r e t o d e l Pr e s i d e n t e d e l l a Re p u b b l i c a 28 m a r z o d e g l i o r g a n i c o l l e g i a l i e d e g l i a l t r i o r g a n i s m i o p e r
a r t t . 3 e 4 c h e p r e v e d o n o l a c o m p o s i z i o n e d e l Co m i t a t o t e VISTO i l d e c r e t o d e l Mi n i s t r o d e l l a s a l u t e 8 a g o s t o 0000, x x x x x Xx n i s t e r o d e l l a s a l u t e i n d a t a 13 a g o s t o 0000, x x x t o n . 9 r i p a r t i z i o n e d e i c o m p o n e n t i t r a l e s e z i o n i d e l Co m i t a VISTO i l d e c r e t o d e l Mi n i s t r o d e l l a s a l u t e 15 d i c e m b r e 0000 x x x x x x x x Xx n i s t e r o d e l l a s a l u t e i n d a t a 7 g e n n a i o 2022, v t e c n i c o s a n i t a r i o , a v e n t e u n a d u r a t a d i t r e a n n i d a l l a VISTO i l Re g o l a m e n t o (UE) 2021/241 d e l Pa r l a m e n t o e u r o p e o e d e l
i s t i t u i s c e i l d i s p o s i t i v o p e r l a r i p r e s a e l a r e s i l i e VISTO i l Pi a n o Na z i o n a l e d i Ri p r e s a e Re s i l i e n z a (PNRR) v a l Co n s i g l i o ECOFIN d e l 13 l u g l i o 2021, n o t i f i c a t a a l l ’ It a l i a d n o t a LT161/21, d e l 14 l u g l i o 2021, e d i n p a r t i c o l a r e l a Mi s s i o “ Va l o r i z z a z i o n e e p o t e n z i a m e n t o d e l l a r i c e r c a b i o m e
d e l l a r i c e r c a b i o m e d i c a t r a m i t e d u e l i n e e d i i n t e r v e (Po C), s o s t e n e n d o l o s v i l u p p o d i t e c n o l o g i e c o n u n b a s s o i l t r a s f e r i m e n t o d i t e c n o l o g i e v e r s o l 'i n d u s t r i a ; b ) i l c a m p o d e l l e m a l a t t i e r a r e e d e i t u m o r i r a r i e d i a l t r e VISTO i l Re g o l a m e n t o (UE) 2018/1046 d e l 18 l u g l i o 2018, c h e s t a b i l i s a l b i l a n c i o g e n e r a l e d e l l ’ Un i o n e , c h e m o d i f i c a i Re g 1303/2013, n . 1304/2013, n . 1309/2013, n . 1316/2013, n . 223/2014, n . 283/2014 e l a d e c i s i
541/2014/UE e a b r o g a i l r e g o l a m e n t o (UE, Eu r a t o m ) n . 966/2012;
VISTO i l d e c r e t o l e g g e d e l 31 m a g g i o 2021, n . 77, c o n v e r t i t o c o 2021, n . 108 « Go v e r n a n c e d e l Pi a n o n a z i o n a l e d i r i p r e s a e r e d e l l e s t r u t t u r e a m m i n i s t r a t i v e e d i a c c e l e r a z i o n e e VISTO i l d e c r e t o d e l Pr e s i d e n t e d e l Co n s i g l i o d e i m i n i s t a m m i n i s t r a z i o n i c e n t r a l i t i t o l a r i d i i n t e r v e n t i p r
c i t a t o d e c r e t o l e g g e 31 m a g g i o 2021, n . 77, c o n v e r t i t o , c o n m 108;
VISTO i l d e c r e t o d e l Mi n i s t r o d e l l ’ e c o n o m i a e d e l l e f i n d e l l e r i s o r s e i n f a v o r e d i c i a s c u n a Am m i n i s t r a z i o n e m i l e s t o n e e t a r g e t ;
VISTO i l d e c r e t o d e l Mi n i s t r o d e l l a s a l u t e , d i c o n c e r t o c s e t t e m b r e 2021, d i i s t i t u z i o n e d e l l ’ Un i t à d i Mi s s i o n e PNRR, a i s e n s i d e l l ’ a r t i c o l o 8 d e l c i t a t o d e c r e t o l e g g e n VISTO l ’ a t t o d i i n d i r i z z o d e l Mi n i s t r o d e l 12 o t t o b r e 2021 So g g e t t i At t u a t o r i n e l l ’ a m b i t o d e g l i i n t e r v e n t i e s u r i p r e s a e r e s i l i e n z a (PNRR) a t i t o l a r i t à d e l Mi n i s t e r o d VISTO i l d e c r e t o l e g g e 6 n o v e m b r e 2021, n . 152 “ Di s p o s i z i o n i n a z i o n a l e d i r i p r e s a e r e s i l i e n z a (PNRR) e p e r l a p r e v e n z VISTA l a l e g g e 16 g e n n a i o 2003, n . 3 “ Di s p o s i z i o n i o r d i n a a m m i n i s t r a z i o n e ” e , i n p a r t i c o l a r e , l ’ a r t i c o l o 11, c o m m a n c h e d i n a t u r a r e g o l a m e n t a r e a d o t t a t i d a l l e Am m i n i s l e g i s l a t i v o 30 m a r z o 2001, n . 165, c h e d i s p o n g o n o i l f i n a n z i a d i p r o g e t t i d i i n v e s t i m e n t o p u b b l i c o , s o n o n u l l i i n a s
c o s t i t u i s c o n o e l e m e n t o e s s e n z i a l e d e l l 'a t t o s t e s s o ” VISTA l a d e l i b e r a d e l CIPE n . 63 d e l 00 x x x x x x r e 2020 c h e i n t r o d u c d e l CUP;
VISTO l ’ a r t i c o l o 1, c o m m a 1042, d e l l a l e g g e 30 d i c e m b r e 2020, n . 1 d e c r e t i d e l Mi n i s t r o d e l l ’ e c o n o m i a e d e l l e f i n a n z e s o l a g e s t i o n e d e l l e r i s o r s e d i c u i a i c o m m i d a 1037 a 1050, n o g e s t i o n e d e l Fo n d o d i c u i a l c o m m a 1037;
VISTO l ’ a r t i c o l o 1, c o m m a 1043, s e c o n d o p e r i o d o , d e l l a l e g g q u a l e a l f i n e d i s u p p o r t a r e l e a t t i v i t à d i g e s t i o n e , d i c o m p o n e n t i d e l Ne x t Ge n e r a t i o n EU, i l Mi n i s t e r o d e l l 'e Ra g i o n e r i a g e n e r a l e d e l l o St a t o s v i l u p p a e r e n d e d i s p VISTO l ’ a r t i c o l o 17 d e l Re g o l a m e n t o (UE) 2020/852 c h e d e f i n i s c p r i n c i p i o d i n o n a r r e c a r e u n d a n n o s i g n i f i c a t i v o (DNSH d e l l a Co m m i s s i o n e UE 2021/C 58/01“ Or i e n t a m e n t i t e c n i c i s u l l u n d a n n o s i g n i f i c a t i v o » a n o r m a d e l r e g o l a m e n t o s u l d VISTI i p r i n c i p i t r a s v e r s a l i p r e v i s t i d a l PNRR, q u a l i , t r a c l i m a t i c o e d i g i t a l e (c .d . t a g g i n g ), i l p r i n c i p i o d i p a r i d e i g i o v a n i ;
VISTI g l i o b b l i g h i d i a s s i c u r a r e i l c o n s e g u i m e n t o d i t a r n e l PNRR;
VISTO i l Re g o l a m e n t o d e l e g a t o (UE) 2021/2106 d e l l a Co m m i s s i o n e i l r e g o l a m e n t o (UE) 2021/241 d e l Pa r l a m e n t o e u r o p e o e d e l Co n r i p r e s a e l a r e s i l i e n z a , s t a b i l e n d o g l i i n d i c a t o r i c o d e l l a r i p r e s a e d e l l a r e s i l i e n z a , c h e p r e v e d e , i n p a r t i g l i i n d i c a t o r i c o m u n i , s i a a g g i o r n a t o i n m o d o c o e r e n t
r i f e r i s c o n o a l l a Co m m i s s i o n e d u e v o l t e l ’ a n n o n e l l ’ a n e l l a r e a l i z z a z i o n e d e i p i a n i p e r l a r i p r e s a e l a r e s i
c o m u n i .”
VISTE l e “ Li n e e Gu i d a p e r l o s v o l g i m e n t o d e l l e a t t i v i t à c
d a l Se r v i z i o Ce n t r a l e p e r i l PNRR, p r e s s o i l Mi n i s t e r o Di p a r t i m e n t o Ra g i o n e r i a g e n e r a l e d e l l o St a t o (RGS), c h
i n f o r mRa et Gi”iv Sso v “i l u p p a t o d a l Mi n i s t e r o d e l l ’ e c o n o m i a e Ra g i o n e r i a Ge n e r a l e d e l l o St a t o i n a t t u a z i o n e d e l l ’ a r n . 178;
VISTO i l d o c u m e n t o “ Si s t e m a d i Ge s t i o n e e Co n t r o l l o (Si .G a d o t t a t o c o n De c r e t o d e l 29 l u g l i o 2022;
VISTE l e “ Li n e e Gu i d a p e r l o s v o l g i m e n t o d e l l e a t t i v i t à d d i c o m p e t e n z a d e l l e Am m i n i s t r a z i o n i c e n t r a l i e d e i So p e r i l PNRR, p r e s s o i l Mi n i s t e r o d e l l ’ e c o n o m i a e d e l l e f i d e l l o St a t o (RGS), c h e c o n t e n g o n o i n d i c a z i o n i p r o c e d u r a c o n t r o l l o e r e n d i c o n t a z i o n e d e l l e s p e s e e d i Mi l e s t o n n o r m a t i v a c o m u n i t a r i a e n a z i o n a l e a p p l i c a b i l e a l PNR 77 d e l 31 m a g g i o 2021, c o m e m o d i f i c a t o d a l l a l e g g e d i c o n v e r VISTO i l d e c r e t o d e l Pr e s i d e n t e d e l Co n s i g l i o d e i Mi n i s s t r u m e n t i p e r i l c o n f e r i m e n t o d e i d a t i ” ;
VISTA l a Ci r c o l a r e MEF-RGS d e l 14 o t t o b r e 2021, n . 21 “ Pi a n o Na z i (PNRR) - Tr a s m i s s i o n e d e l l e Is t r u z i o n i Te c n i c h e p e r l a s e l VISTO i l De c r e t o i n t e r m i n i s t e r i a l e d e l 7 d i c e m b r e 2021 p e r l a p a r i o p p o r t u n i t à d i g e n e r e e g e n e r a z i o n a l i , n o n c h é n e i c o n t r a t t i p u b b l i c i f i n a n z i a t i c o n l e r i s o r s e d e l VISTA l a Ci r c o l a r e MEF-RGS d e l 30 d i c e m b r e 2021, n . 00, x x x x x x e “ Gu
p r i n c i p i o d i n o n a r r e c a r e d a n n o s i g n i f i c a t i v o a l l ’ a m VISTA l a Ci r c o l a r e MEF-RGS d e l 31 d i c e m b r e 2021, n . 33 “ Pi a n o Na z i (PNRR) – No t a d i c h i a r i m e n t o s u l l a Ci r c o l a r e d e l 14 o t t o b r Te c n i c h e p e r l a s e l e z i o n e d e i p r o g e t t i PNRR – Ad d i z i o n a
a s s e n z a d e l c .d . d o p p i o f i n a n z i a m e n t o ”
VISTA l a Ci r c o l a r e MEF-RGS d e l 21 g i u g n o 2022, n . 27 “ Mo n i t o r a g g i VISTA l a Ci r c o l a r e MEF-RGS d e l l ’ 11 a g o s t o 2022, n . 30 s u l l e p r o c e d e l l e m i s u r e PNRR;
VISTA l a Co m u n i c a z i o n e d e l l a Co m m i s s i o n e 2014/C 198/01 “ Di s c i p r i c e r c a , s v i l u p p o e i n n o v a z i o n e ” e s .m .i .;
VISTO i l Re g o l a m e n t o (UE) n . 651/2014 d e l l a Co m m i s s i o n e , d e l 17 g i c a t e g o r i e d i a i u t i c o m p a t i b i l i c o n i l m e r c a t o i n t e r n VISTA l a c o m u n i c a z i o n e d e l l a Co m m i s s i o n e 2016/C 262/01 s u l l a a l l 'a r t i c o l o 107, p a r a g r a f o 1, d e l t r a t t a t o s u l f u n z i o n a m VISTA l a Co m u n i c a z i o n e d e l l a Co m m i s s i o n e d e l 19 m a r z o 2020, C l e m i s u r e d i a i u t o d i St a t o a s o s t e g n o d e l l 'e c o n o m i a n e r e t t i f i c a t a a t t r a v e r s o l a c o m u n i c a z i o n e d e l 00 x x x x x x t e m p o r a n e o p e r l e m i s u r e d i a i u t o d i St a t o a s o s t e g n o d 19 e m o d i f i c a d e l l 'a l l e g a t o d e l l a c o m u n i c a z i o n e d e l l a d e g l i a r t i c o l i 107 e 108 d e l t r a t t a t o s u l f u n z i o n a m e n t o
a l l 'e s p o r t a z i o n e a b r e v e t e r m i n e ” ;
VISTO i l d e c r e t o d e l Mi n i s t r o d e l l a s a l u t e 1° a p r i l e 2022 c
2.1.1 - p r o o f o f c o n c e p t , 2.1.2 – t u m o r i e m a l a t t i e r a r e e 2.1.3 r i p a r t i z i o n e d e g l i i n t e r v e n t i d i i n v e s t i m e n t o d e l l a Na z i o n a l e d i Ri p r e s a e Re s i l i e n z a r e l a t i v o a l l 'i n n o v a z s a n i t a r i o n a z i o n a l e e a l p o t e n z i a m e n t o d e l s i s t e m a d VISTO i l I° a v v i s o p u b b l i c o p e r l a p r e s e n t a z i o n e e s e l
n e l l ’ a m b i t o d e l PNRR, p u b b l i c a t o s u l s i t o w e b d e l Mi n i s t u f f i c i a l e d e l l a Re p u b b l i c a i t a l i a n a , s u l l e s e g u e n t i t c o n e s c l u s i o n e d e i t u m o r i r a r i , Ma l a t t i e Cr o n i c h e n o n s a n i t a r i e s o c i o -a s s i s t e n z i a l i (Fa t t o r i d i r i s c h i o e p VISTO i l d e c r e t o d i r e t t o r i a l e n . 27 d e l 2 n o v e m b r e 0000, x x x x x x x x i l a n c i o i n d a t a 18 n o v e m b r e 2022, c o n i l q u a l e è s t a t a a PNRR- Mi s s i o n e 6 - Co m p o n e n t e 2 - In v e s t i m e n t o 2.1, a f f e r e n t i Co n c e p t , Ma l a t t i e r a r e , Ma l a t t i e c r o n i c h e n o n t r a s m i s
a s s i s t e n z i a l i (t e m a t i c h e : Fa t t o r i d i r i s c h i o e p r e v e n i l q u a l e s i è p r o c e d u t o a d i n d i v i d u a r e i l So g g e t t o a t t VISTO l ’ a r t . 7 d e l d e c r e t o m i n i s t e r i a l e 8 a p r i l e 2015, r e c a n t n o n g e n e r a l e d e l Mi n i s t e r o d e l l a s a l u t e , o v e v e n g o n o i
g e n e r a l e d e l l a r i c e r c a e d e l l ’ i n n o v a z i o n e i n s a n i t à u f f i c i 3 e 4 d e l l a s t e s s a ;
VISTO i l d e c r e t o d i r e t t o r i a l e d e l 1° m a r z o 2022, r e g i s t r a t m a r z o 2022, a l n . 247, c o n i l q u a l e i l Do t t . Ga e t a n o Gu x x x x x x x è d e l p o t e r e d i s p e s a e l ’ o r d i n e d i s e r v i z i o c o n i l q u a l e p e r i p r o g e t t i r i s u l t a t i v i n c i t o r i n e l b a n d o PNRR;
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p r o g e t t u a l e h a a v u t o e s i t o p o s i t i v o e c h e , p e r t a n t o , l a
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2. La p r e s e n t e Co n v e n z i o n e d e f i n i s c e , t r a l ’ a l t r o , g l i o e q u e l l e d i p a g a m e n t o .
3. Il s o g g e t t o a t t u a t o r e -b e n e f i c i a r i o e i l Pr i n c i p a l In q u a n t o r i p o r t a t o n e l p r o g e t t o p r e s e n t a t o p a r t e i n t Mi n i s t e r o e i n o t t e m p e r a n z a a q u a n t o p r e v i s t o d a l l ’
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1. La p r e s e n t e c o n v e n z i o n e h a l a d u r a t a d i 24 m e s i p r o r o g p r e v i s t o d a l s u c c e s s i v o a r t i c o l o 11.
2. L’ a t t i v i t à d i r i c e r c a , d a s v o l g e r s i n e l l ’ a r c o t e m p o i n i z i o i m p r o r o g a b i l m e n t e e n t r o e n o n o l t r e i l 20 m a g g c o n n o t a s o t t o s c r i t t a d i g i t a l m e n t e d a l p r o p r i o r a p r i c e r c a c h e d e v e e s s e r e t r a s m e s s a a l m e n o 30 g i o r n i d o c u m e n t a z i o n e d i c u i a l s u c c e s s i v o c o m m a 4.
3. Il So g g e t t o b e n e f i c i a r i o e n t r o e n o n o l t r e 15 g i o r n i d a Mi n i s t e r o p e r l a s o t t o s c r i z i o n e p r o v v e d e a l l a r e s r a p p r e s e n t a t e e c o n t r o f i r m a t a d a l Pr i n c i p a l In v e s t i a c c o m p a g n a t a d a l l a c o m u n i c a z i o n e d e l c o d i c e CUP MAST s i n g o l e Un i t à o p e r a t i v e . Le p a r t i r i c o n o s c o n o c h e i l
d a l f i n a n z i a m e n t o i n c a s o d i i n a d e m p i e n z a d e l l a p r e
4. Il So g g e t t o b e n e f i c i a r i o , e n t r o e n o n o l t r e 30 g i o r n i p r 2 d e l p r e s e n t e a r t i c o l o , p e n a l a d e c a d e n z a d a l f i n a s o t t o s c r i t t a d i g i t a l m e n t e i n m a n i e r a c o n g i u n t a d In v e s t i g a t o r d e l l a r i c e r c a - l a s e g u e n t e d o c u m e n t a z f i n e d i a u t o r i z z a r e l ’ a v v i o d e l p r o g e t t o :
a ) l a d i c h i a r a z i o n e d a p a r t e d e l l e g a l e r a p p r e s e d i c h i a r i c h e i l p r o g e t t o i n q u e s t i o n e o p a r t i s
f i n a n z i a m e n t i p u b b l i c i a f a v o r e d e l l ’ En t e a t t u e c h e , i n o g n i c a s o , s a r à p o s t a i n e s s e r e o g n i i f i n a n z i a m e n t o ;
b ) l a d i c h i a r a z i o n e d a p a r t e d e l l e g a l e r a p p r e s e n u n i t à o p e r a t i v a p a r t e c i p a n t e c o n c u i s i d i c h i p r o g e t t o i n q u e s t i o n e o p e r p a r t i s i g n i f i c a t f i n a n z i a m e n t i p u b b l i c i a f a v o r e d e l l ’ Un i t à o p e o p e r a t i v e e l e n c a t i n e l l a p r o p o s t a p r o g e t t u a l
i n i z i a t i v a v o l t a a d e v i t a r e i l d o p p i o f i n a n z i a c ) l a d i c h i a r a z i o n e d a p a r t e d e g l i En t i c h e s v o l g o
r e s p o n s a b i l i d i a c c e t t a z i o n e d e i t e r m i n i d e l l d ) l a d i c h i a r a z i o n e c o n l a q u a l e i l So g g e t t o b e n e f
s v o l g e r à l a p r o p r i a a t t i v i t à d i r i c e r c a , p e r l p r o g e t t o , e s c l u s i v a m e n t e p r e s s o l a p r o p r i a s e d m e d e s i m o , c o n t r o f i r m a t a d a l l ’ i n t e r e s s a t o ;
e ) i l p a r e r e p o s i t i v o d e l Co m i t a t o e t i c o c o m p e t e n d e l d e c r e t o l e g i s l a t i v o n . 26 d e l 4 m a r z o 2014 r i g u a r p r e v i s t i ;
f ) l a c o m u n i c a z i o n e d e l c o d i c e CUP d e l l e s i n g o l e Un i l c o d i c e f i s c a l e d e i s o g g e t t i d e s i g n a t i a o p e f o r m a t e x c e l c h e v e r r à c o n d i v i s o d a p a r t e d e d e l l ’ i n n o v a z i o n e i n s a n i t à c h e d o v r à e s s e r e r e
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5. Pe r l a r e a l i z z a z i o n e d e l l e a t t i v i t à 1,.l00’0.0i00m,0p0€o(Eru tr oo a m m e s
u n m i l i ) oa nv ea /0l 0 e r e s u l l e r i s o r s e a s s e g n a t e p e r l e t e m a t t a b e l l a a l l e g a t a a l d e c r e t o m i n i s t e r i a l e 1° a p r i l e 2 r i p a r t i z i o n e d e g l i i n t e r v e n t i d i i n v e s t i m e n t o d e l l Pi a n o Na z i o n a l e d i Ri p r e s a e Re s i l i e n z a r e l a t i v o a l l ' d e l Se r v i z i o s a n i t a r i o n a z i o n a l e e a l p o t e n z i a m e n t o
6. La p r e s e n t a z i o n e d e l l a r i c h i e s t a d i p a g a m e n t o d e l l a l e m o d a l i t à p r e v i s t e d a l l ’ a r t . 13, p a r a g r a f o 13.1 d e l b a n d e l l a d o c u m e n t a z i o n e a s u p p o r t o n e l s i s t e m a Re Gi S, e n d a p a r t e d e l Mi n i s t e r o d e l l ’ a p p r o v a z i o n e d e l l a r e l
7. La p r e s e n t a z i o n e d e l l a r i c h i e s t a d i p a g a m e n t o f i n a s u c c e s s i v a m e n t e a l l ’ i n v i o e n t r o 30 g i o r n i d a l l a d a p r o r o g a t a s e c o n d o i t e r m i n i d e l l a p r e s e n t e c o n v e n z i r e n d i c o n t a z i o n e e c o n o m i c a c o m p l e s s i v a d e l p r o g e t t d a p a r t e d e l Mi n i s t e r o d e l l ’ a p p r o v a z i o n e d e l l a r e l
8. Il m a n c a t o a d e m p i m e n t o d i q u a n t o p r e v i s t o d a i c o m m i 2 a r e a l i z z a r e i l p r o g e t t o e c o m p o r t a l a d e c a d e n z a
f i n a n z i a m e n t o .
Ar t . 5 Ob b l i g h i d e l So g g e t t o a t t u a t o r e -b e n e f i c i a r i o
1. Co n l a s o t t o s c r i z i o n e d e l l a p r e s e n t e Co n v e n z i o n e , i In v e s t i g a t o r , p e r q u a n t o d i c o m p e t e n z a , s i o b b l i g a n o
1) a s s i c u r a r e i l r i s p e t t o d i t u t t e l e d i s p o s i z i o n i p r p a r t i c o l a r e r i f e r i m e n t o a q u a n t o p r e v i s t o d a l Re g . c o n v e r t i t o c o n m o d i f i c a z i o n i d a l l a L. 29 l u g l i o 2021, n .
2) g a r a n t i r e i l r i s p e t t o d i e v e n t u a l i p r e v i s i o n i n o r Mi n i s t e r o d e l l a s a l u t e , d a l Mi n i s t e r o d e l l ’ e c o n o m o v v e r o d a a l t r i s o g g e t t i c o i n v o l t i n e l l ’ a t t u a z i o n a n c h e s u c c e s s i v a m e n t e a l l a s o t t o s c r i z i o n e d e l l a p
3) a s s i c u r a r e l ’ a d o z i o n e d i m i s u r e a d e g u a t e v o l t e a r s e c o n d o q u a n t o d i s c i p l i n a t o n e l Re g o l a m e n t o f i n a n d e l Re g o l a m e n t o (UE) 2021/241, i n p a r t i c o l a r e i n m a t e r i a d
i n t e r e s s i , d e l l e f r o d i , d e l l a c o r r u z i o n e , d e l d o p p i f o n d i c h e s o n o s t a t i i n d e b i t a m e n t e a s s e g n a t i ;
4) r i s p e t t a r e , a p e n a d i s o s p e n s i o n e o r e v o c a d e l f i n p r i n c i p i o d i “ n o n a r r e c a r e d a n n o s i g n i f i c a t i v o ” d e l l ’ a r t i c o l o 17 d e l Re g o l a m e n t o (UE) 2020/852, i p r i n c i p i
l ’ a l t r o , i l p r i n c i p i o d e l c o n t r i b u t o a l l ’ o b i e t t i v p r o d u c e n d o d a t i r e l a t i v i a i d e s t i n a t a r i e f f e t t i
r e l a z i o n e a g l i a r t i c o l i 2, 3, p a r a g r a f o 3, d e l TUE, 8, 10, 19 e d e i d i r i t t i f o n d a m e n t a x x x x x x ’ Un i o n e e u r o p e a ), l ’ o e d e v e n t u a l i u l t e r i o r i r e q u i s i t i e c o n d i z i o n a l i t Co n v e n z i o n e ;
5) a d o t t a r e p r o p r i e p r o c e d u r e i n t e r n e , a s s i c u r a n d o l i n d i c a t o d a l Mi n i s t e r o n e l l a d e s c r i z i o n e d e l l e f u
6) d a r e p i e n a a t t u a z i o n e a l p r o g e t t o c o s ì c o m e i l l u f i n a n z i a m e n t o d a l Mi n i s t e r o , g a r a n t e n d o l ’ a v v i o
i n c o r r e r e i n r i t a r d i a t t u a t i v i e c o n c l u d e r e i l p r o r i s p e t t o d e l l a t e m p i s t i c a p r e v i s t a d a l r e l a t i v o Mi n i s t e r o l e e v e n t u a l i m o d i f i c h e a l p r o g e t t o ;
7) a s s i c u r a r e i l r i s p e t t o d e l l a n o r m a t i v a v i g e n t e s u
8) a s s i c u r a r e i l r i s p e t t o d e i c r i t e r i d i a m m i s s i b i l d a l l ’ Av v i s o p e r l e v a r i e v o c i d i c o s t o , c h e s a r a n n o c a l n e t t o d i e v e n t u a l i e c o n o m i e r i s c o n t r a t e s u l f i n d o p o v e r i f i c a d a p a r t e d e l Mi n i s t e r o ;
9) g a r a n t i r e , n e l c a s o i n c u i s i f a c c i a r i c o r s o a l l e p r d e c r e t o l e g i s l a t i v o n . 50/2016 e s .m .i .; r i s p e t t a r e , i n c a l l ’ Am m i n i s t r a z i o n e , l a c o n f o r m i t à a l l a p e r t i n e n t
e v e n t u a l i s p e c i f i c h e c i r c o l a r i /d i s c i p l i n a r i c h e p
10) i n d i v i d u a r e e v e n t u a l i f a t t o r i c h e p o s s a n o d e t e r m i s u l l a t e m p i s t i c a a t t u a t i v a e d i s p e s a d e f i n i t a n e l s t e s s i ;
11) m i t i g a r e e g e s t i r e i r i s c h i c o n n e s s i a l p r o g e t t o
a l l ’ a n d a m e n t o g e s t i o n a l e e d a l l e c a r a t t e r i s t i c h e
12) e f f e t t u a r e i c o n t r o l l i o r d i n a r i d i g e s t i o n e e d i
n o r m a t i v a v i g e n t e , e l e v e r i f i c h e s u l c o n f l i t t o d i i d a l l a n o r m a t i v a a n t i r i c i c l a g g i o (“ t i t o l a r e e f f e t t
13) u t i l i z z a r e i l s i s t e m a i n f o r m a t i c o “ Re Gi S, f i n a l i z z a e l e t t r o n i c o i d a t i p e r c i a s c u n a o p e r a z i o n e n e c e s s
f i n a n z i a r i a , l a v e r i f i c a e l ’ a u d i t , s e c o n d o q u a n t o (UE) 2021/241 e t e n e n d o c o n t o d e l l e i n d i c a z i o n i c h e v e r r a i l t r a m i t e d e l Mi n i s t e r o ;
14) c a r i c a r e s u l p o r t a l e Wo r k f l o w d e l l a Ri c e r c a e n e l s c i e n t i f i c a s u l l o s t a t o d i a v a n z a m e n t o d e l p r o g e t s t e s s o ;
15) c a r i c a r e s u l s i s t e m a i n f o r m a t i v o “ Re Gi S” l a d o c u
s v o l g i m e n t o d e i c o n t r o l l i o r d i n a r i p r e v i s t i d a l l a e s p l e t a t e p e r l ’ a g g i u d i c a z i o n e d e g l i e v e n t u a l i a p r i c h i e s t a d a l l e Am m i n i s t r a z i o n i c e n t r a l i d e p u t a t
16) g a r a n t i r e l a c o r r e t t e z z a , l ’ a f f i d a b i l i t à e l a c o n l ’ a l i m e n t a z i o n e d e l s i s t e m a i n f o r m a t i v o “ Re Gi S” d e a i CUP d e l l e s i n g o l e Un i t à o p e r a t i v e s u l l ’ a v a n z a m e n c h e c o m p r o v a n o i l c o n s e g u i m e n t o d e g l i o b i e t t i v i
i n d i c a t o r i a d o t t a t i p e r l e m i l e s t o n e s e i t a r g e t d e a l m e n o b i m e s t r a l e d e l l e s p e s e (n e l t e r m i n e m a s s i m o b i m e s t r e ) n e l p o r t a l e Wo r k f l o w d e l l a Ri c e r c a e s u l
d o c u m e n t a z i o n e p r o b a t o r i a p e r t i n e n t e , s a l v o d i v e r
17) r i s p e t t a r e l ’ o b b l i g o d i i n d i c a z i o n e d e l CUP s u t u t p r o g e t t o e s u i d o c u m e n t i c o l l e g a t i a l l e r e l a t i v e p
18) f o r n i r e t u t t e l e i n f o r m a z i o n i r i c h i e s t e r e l a t i v a
s p e s e r e n d i c o n t a t e c o n f o r m e m e n t e a l l e p r o c e d u r e e
19) g a r a n t i r e l a c o n s e r v a z i o n e d e l l a d o c u m e n t a z i o n e p a s s i c u r a r e l a c o m p l e t a t r a c c i a b i l i t à d e l l e o p e r a z 4, d e l D.L. n . 77 d e l 31 m a g g i o 2021, c o n v e r t i t o c o n m o d i f i c a z d i v e r s e f a s i d i c o n t r o l l o e v e r i f i c a p r e v i s t e d a l s e s s e r e m e s s i p r o n t a m e n t e a d i s p o s i z i o n e s u r i c h i
i n t e r v e n t o PNRR, d e l Se r v i z i o c e n t r a l e p e r i l PNRR d Co m m i s s i o n e e u r o p e a , d e l l ’ OLAF, d e l l a Co r t e d e i Co n t i (EPPO) e d e l l e c o m p e t e n t i Au t o r i t à g i u d i z i a r i e n a z i o n Co r t e d e i c o n t i e l 'EPPO a e s e r c i t a r e i d i r i t t i d i c u i
f i n a n z i a r i o (UE; XXXXXXX) 1046/2018;
20) f a c i l i t a r e l e v e r i f i c h e d e l l ’ Uf f i c i o c o m p e t e n t e p Co m m i s s i o n e e u r o p e a e d i a l t r i o r g a n i s m i a u t o r i z z a a t t r a v e r s o c o n t r o l l i i n l o c o ;
21) a s s i c u r a r e c h e l e s p e s e d e l Pr o g e t t o d i r i c e r c a n o f i n a n z i a m e n t i , c o n t r i b u t i o a g e v o l a z i o n i a v a l e r e d e l d o p p i o f i n a n z i a m e n t o );
22) g a r a n t i r e l a d i s p o n i b i l i t à d e i d o c u m e n t i g i u s t i f i c o s ì c o m e p r e v i s t o a i s e n s i d e l l ’ a r t i c o l o 9 p u n t o 4 d i n l e g g e 29 l u g l i o 2021, n . 108;
23) p r e d i s p o r r e i p a g a m e n t i s e c o n d o l e p r o c e d u r e s t a f i n a n z i a r i o e c r o n o g r a m m a d i s p e s a a p p r o v a t o , i n s e e v e n t u a l m e n t e d i 6 m e s i ) n e l p o r t a l e Wo r k f l o w d e l l a r e l a t i v i d o c u m e n t i r i f e r i t i a l l e p r o c e d u r e e i g i u o r d i n a r i d i l e g a l i t à e a i c o n t r o l l i a m m i n i s t r a t i a p p l i c a b i l e , n e l r i s p e t t o d i q u a n t o p r e v i s t o d a l l ’ d e l d e c r e t o l e g g e n . 77 d e l 31/05/2021, c o n v e r t i t o i n l e g g e 2
24) a s s i c u r a r e c h e t u t t e l e s p e s e r e n d i c o n t a t e s i a n o s p r o g e t t o e c h e g l i e v e n t u a l i p a g a m e n t i p e r f a t t u r e s i a n o c o m p l e t a t e e n t r o i 30 g i o r n i s u c c e s s i v i a l l a c a r i c a m e n t o s u l s i s t e m a d i r e n d i c o n t a z i o n e Re Gi S;
25) i n o l t r a r e , a l l o s c a d e r e d e i 12 e 24 m e s i (p r o r o g a b i l i p a g a m e n t o a l Mi n i s t e r o t r a m i t e i l p o r t a l e Wo r k f l “ Re Gi S” c o n a l l e g a t a l a r e n d i c o n t a z i o n e d e t t a g l i a c o n t r i b u t o a l p e r s e g u i m e n t o d e l l e m i l e s t o n e s e d e i u n i t a m e n t e a i d o c u m e n t i g i u s t i f i c a t i v i a p p r o p r i a d i s p o s i t i v i a t t u a t i v i ;
26) g a r a n t i r e l ’ u t i l i z z o d i u n c o n t o c o r r e n t e d e d i c a l ’ a d o z i o n e d i u n a c o n t a b i l i t à s e p a r a t a o d i u n ’ a p p t u t t e l e t r a n s a z i o n i r e l a t i v e a l p r o g e t t o a l f i n e d d e l PNRR;
27) a s s i c u r a r e , d i r e t t a m e n t e o a t t r a v e r s o l e Is t i t u z i o d i r i c e r c a , l ’ a n t i c i p a z i o n e d e l l e s o m m e n e c e s s a r i
28) p a r t e c i p a r e , o v e r i c h i e s t o , a l l e r i u n i o n i c o n v o c a t
29) g a r a n t i r e , a n c h e a t t r a v e r s o l a t r a s m i s s i o n e d i r e l p r o g e t t o , c h e i l Mi n i s t e r o r i c e v a t u t t e l e i n f o r m a z l ’ e l a b o r a z i o n e d e l l e r e l a z i o n i a n n u a l i d i c u i a l l n o n c h é q u a l s i a s i a l t r a i n f o r m a z i o n e e v e n t u a l m e n t
30) c o n s e g u i r e i l r a g g i u n g i m e n t o d e g l i o b i e t t i v i d e l l a d o t t a t i p e r l e m i l e s t o n e s e i t a r g e t d e l l a m i s u r a Mi n i s t e r o , l e i n f o r m a z i o n i n e c e s s a r i e p e r l a p r e d i d i t a r g e t e m i l e s t o n e s e d e l l e r e l a z i o n i e d o c u m e n t
31) g a r a n t i r e i l r i s p e t t o d e g l i o b b l i g h i i n m a t e r i a d i d e l Re g o l a m e n t o (UE) 2021/241 i n d i c a n d o n e l l a d o c u m e n t a f i n a n z i a t o n e l l ’ a m b i t o d e l PNRR, c o n e s p l i c i t o r i f e
e u r o p e a e a l l ’ i n i z i a t i v a Ne x t Ge n e r a t i o n EU (a d e s . u e u r o p e a – Ne x t Ge n e r a t i o n EU – PNRR M6C2 - In v e s t i m e n t o 2.1 d e l l a r i c e r c a b i o m e d i c a d e l SSN” ), r i p o r t a n d o n e l l a d e u r o p e a e f o r n i r e u n ’ a d e g u a t a d i f f u s i o n e e p r o m o z i i n l i n e a c o n q u a n t o p r e v i s t o d a l l a St r a t e g i a d i Co m u
32) f o r n i r e i d o c u m e n t i e l e i n f o r m a z i o n i n e c e s s a r i e s t a b i l i t e d a i Re g o l a m e n t i c o m u n i t a r i e d a l Mi n i s t e
33) g a r a n t i r e u n a t e m p e s t i v a d i r e t t a i n f o r m a z i o n e a g l s u l l ’ a v v i o e l ’ a n d a m e n t o d i e v e n t u a l i p r o c e d i m e a m m i n i s t r a t i v o c h e d o v e s s e r o i n t e r e s s a r e l e o p e
i r r e g o l a r i t à , l e f r o d i , i c a s i d i c o r r u z i o n e e d i c f i n a n z i a m e n t o , r i s c o n t r a t i a s e g u i t o d e l l e v e r i f i
n | e | l | r i s p e t t o d e l l e p r o c e d u r e a d o t t a t e d a l l o s t e s s |
d | e | l | Re g o l a m e n t o (UE) 2021/2041; |
34) g | a | r | a n t i r e c h e i l Mi n i s t e r o r i c e v a a t t r a v e r s o i l s i |
l | ’ | a | g g i o r n a m e n t o d e l l ’ i n d i c a t o r e c o m u n e n . 8 “ Ri c e |
b | e | n | e f i c i a r i d i u n s o s t e g n o ” , r i c o n d u c i b i l e a l l a m i |
a | i | s | e n s i d e l l ’ a r t . 3, c o m m a 3, d e l Re g o l a m e n t o d e l e g a t o |
s | e | t | t e m b r e 2021 c h e i n t e g r a i l r e g o l a m e n t o (UE) 2021/241 d e l |
c | h | e | i s t i t u i s c e i l d i s p o s i t i v o p e r l a r i p r e s a e l a |
l | ’ | a | g g i o r n a m e n t o d e g l i i n d i c a t o r i c o m u n i h a l u o g o |
p | e | r | i o d o d i r i f e r i m e n t o c o p r e l ’ i n t e r o p e r i o d o d i a |
d | e | l | c a s o , f i n o a l l e r i s p e t t i v e d a t e l i m i t i d e l 31 d i c |
Ar t . 6 Pr o c e d u r a d i m o n i t o r a g g i o e r e n d i c o n t a z i o n e
1. Il Mi n i s ct oe nr lo a p r e s e n t e c o n v e n z i o n e r a p p r e s e n t a a l l a s c i e n t i f i c o s a r à s v o l t o d a l l a Di r e z i o n e d e l l a Ri c e r i s p e t t o a l l a r e n d i c o n t a z i o n e d e l l e s p e s e s a r a n n o
i n t e r v e n t pi r de es ls oPNiRRl Mi n i s t e r o d e l l a s a l u t e .
2. Il So g g e t t o a t t u a t o r e -b e n e f i c i a r i o , s e c o n d o l e i n d i c a l m e n o b i m e s t r a l e , e n t r o 10 g i o r n i s u c c e s s i v i a l l ’ s u l l ’ a v a n z a m e n t o f i n a n z i a r i o , f i s i c o e p r o c e d u r a l i m p l e m e n t a r e t a l e s i s t e m a c o n l a d o c u m e n t a z i o n e a f f i d a m e n t o e a c i a s c u n a t t o g i u s t i f i c a t i v o d i s p e s d e i c o n t r o l l i a m m i n i s t r a t i v o -c o n t a b i l i a n o r m a d e l
d i m i s s i o n e p e r l 'a t t u a z i
po rn ee sdMsei gonl ii i sl it
ne tr
eo rdveel nl t a i s da el l u Pt NeR
3. Il So g g e t t o a t t u a t o r e -b e n e f i c i a r i o , a l l o s c a d e r e d e i d e v e t r a s m e t t e r e i d a t i s u l l ’ a v a n z a m e n t o t e c n i c o -s d e l l a Ri c e r c a e i l s i s t e m a “ Re Gi S” c o r r e d a t a d i d o c u m e d i a f f i d a m e n t o e a c i a s c u n a t t o g i u s t i f i c a t i v o d i l ’ e s p l e t a m e n t o d e i c o n t r o l l i a m m i n i s t r a t i v o -c o n t a p r o g e t t o .
4. Il So g g e t t o a t t u a t o r e -b e n e f i c i a r i o , p e r t a n t o , d o v r à i e v e n t u a l m e n t e d i 6 m e s i ) t r a m i t e i l p o r t a l e Wo r k f l o w l a r i c h i e s t a r e n d i c o n t a z i o n e d e l l e s p e s e v o l t e a s e s s e r e f o r m a l m e n t e t r a s m e s s e a l l ’ Un i t à d i Mi s s i o n e s p e s e e f f e t t i v a m e n t e s o s t e n u t e n e l p e r i o d o d i r i f e i n t e r v e n t o /p r o g e t t o c o n s p e c i f i c o r i f e r i m e n t o a l l e e s s e r e c o r r e d a t a d a l l a d o c u m e n t a z i o n e s p e c i f i c a t Mi n i s t e r o .
5. Le s p e s e i n c l u s e n e l l e r i c h i e s t e d i p a g a m e n t o d e l S o p e r a z i o n i e s t r a t t e a c a m p i o n e , s o n o s o t t o p o s t e , p e r v e r i f i c h e , s e d e l c a s o a n c h e i n l o c o d a p a r t e d e l l e s t
6. Ne l l o s p e c i f i c o , l ’ Un i t à d i m i s s i o n e pd ee Mrl i ln 'ai
ts tt
ue ar
zo i doen
Sa l u t e e e v e n t u a l i a l t r e a m m i n i s t r a z i o n i c o i n v o l t e s u l l e p r o c e d u r e , s u l l e s p e s e e s u i t a r g e t i n c o n f o r m i (UE) 2021/241 a l f i n e d i g a r a n t i r e l a t u t e l a d e g l i i n t e r e
i n d i v i d u a z i o n e e r e t t i f i c a d i f r o d i , d i c a s i d i c o r r u s o m m e e r r o n e a m e n t e v e r s a t e o u t i l i z z a t e i n m o d o n o n
7. La Di r e z i o n e g e n e r a l e d e l l a Ri c e r c a e d i n n o v a z i o n e i m e r i t o l e f u n z i o n i d i v e r i f i c a t e c n i c o -s c i e n t i f i c a i n c o e r e n z a c o n l o s t a t o d i r e n d i c o n t a z i o n e d e l l e s p
Ar t . 7 Va l u t a z i o n e i n t e r m e d i a
1. Al l o s c a d e r e d e i 12 m e s i d a l l ’ i n i z i o d e l l ’ a t t i v i t à d d a t a l e t e r m i n e , i l So g g e t t o a t t u a t o r e -b e n e f i c i a r i o d e l l a r i c e r c a l a r e l a z i o n e i n t e r m e d i a s u l l o s t a t o d i g i t a l m e n t e d a l l e g a l e r a p p r e s e n t a n t e d e l So g g e t t
- c o n t e n e n t e l a d e s c r i z i o n e d e l l e a t t i v i t à p r o g e t t o p e r a t i v e , d a c u i r i s u l t i l o s t a t o a v a n z a m e n t o l a v o s e c o n d o q u a n t o r i p o r t a t o n e l p r o g e t t o a p p r o v a t o . Ta l Pr i n c i p a l In v e s t i g a t o r , c h e i l l u s t r i , n e l l a g l o b a l i d e s c r i z i o n e d e l l e a t t i v i t à r e a l i z z a t e d a e v e n t u a l
s u b c o n t r a e n t i .La r e l a z i o n e i n t e r m e d i a , p r e v i a v e r i f Ri c e r c a e d i n n o v a z i o n e i n s a n i t à , s a r à c a r i c a t a d a l In v e s t i g a t o r a l l ’ i n t e r n o d e l s i s t e m a i n f o r m a t i v o “
2. Il Mi n i s t e r o h a f a c o l t à , p r e v i a c o m u n i c a z i o n e p r e v e n l e p r o c e d u r e p e r l a s o s p e n s i o n e d e l f i n a n z i a m e n t o e d e g l i e v e n t u a l i i n t e r e s s i l e g a l i m a t u r a t i , q u a l o r
q u a n t o p r e v i s t o e n t r o i t e r m i n i d i c u i a l c o m m a 1 d e l p
3. La Di r e z i o n e g e n e r a l e d e l l a Ri c e r c a e d i n n o v a z i o n e c o m u n i c a z i o n e p r e v e n t i v a a l So g g e t t o a t t u a t o r e /b e n
m i s s i o n e p e r l 'a t t u a z i o n de ed le gmle id Mie i nsnti iemsrot x xx xx xx , x x xx xx x x XxXXx Rs
c o n d i z i o n i p e r n o n e r o g a r e l e s u c c e s s i v e q u o t e a r i g i u d i z i o i n o r d i n e a l l a r e l a z i o n e f i n a l e , q u a l o r a l
s i a c o n s i d e r a t a i d o n e a a d i m o s t r a r e c h e s i a n o s t a t i e m e r g a c h e e s s a s i a s t a t a c o n d o t t a n o n i n p i e n a c o n f o In t a l c a s o i l Mi n i s t e r o p o t r à p r o c e d e r e c o n i l r i m b t e r m i n i d i c u i a l l a p r e s e n t e c o n v e n z i o n e , c h e n o n c o
So g g e t t o a t t u a t o r e /b e n e f i c i a r i o e s o n e r a i l Mi n i s t e n e l l ’ e r o g a z i o n e d e l l e s o m m e s p e t t a n t i .
4. Il Mi n i s t e r o , p r e v i a c o m u n i c a z i o n e p r e v e n t i v a a l So g Co m i t a t o t e c n i c o s a n i t a r i o s e z . c ), u n d o s s i e r , q u a l o r a m i n i s t e r i a l e , n o n c o n s e n t a d i e s p r i m e r e u n c o m p i u t Co m i t a t o è v i n c o l a n t e p e r i l So g g e t t o b e n e f i c i a r i o a
Ar t . 8 Va l u t a z i o n e f i n a l e
1. Fa t t a s a l v a l ’ e v e n t u a l e c o n c e s s i o n e d i p r o r o g a d e l v e n t i q u a t t r o m e s i - e c o m u n q u e n o n o l t r e t r e n t a (30) g i r i c e r c a – a i f i n i d e l l ’ e r o g a z i o n e d e l s a l d o , i l So g d i g i t a l m e n t e d a l r a p p r e s e n t a n t e l e g a l e , t r a s m e t t
d o c u m e n t a z i o n e , r e d a t t a d a l Pr i n c i p a l In v e s t i g a t o r e
- l a r e l a z i o n e f i n a l e d e l l a r i c e r c a , c o n t e n e n t e q u c o f i n a n z i a t o r i , c h e d o c u m e n t i , p e r c i a s c u n a u n i t à i l p r o g e t t o a p p r o v a t o e g l i o b i e t t i v i r a g g i u n t i ;
- c o p i a d e i l a v o r i p u b b l i c a t i s u r i v i s t e i m p a t t a t e
- l a r e n d i c o n t a z i o n e d e l l e s p e s e s o s t e n u t e c o n i f o
- i n d i c a z i o n i d e l r e p o s i t o r y p u b b l i c o d o v e s o n o r e u t i l i z z a t i p e r l e p u b b l i c a z i o n i s c i e n t i f i c h e c o
- i l r i s p e t t o d e i c o s t i s o s t e n u t i r i s p e t t o a i v i n c o d a p a r t e d i i s t i t u z i o n i n e l l ’ a r e e d e l m e r i d i o n e
2. La r e n d i c o n t a z i o n e e c o n o m i c a d o v r à e s s e r e c o r r e d a t c h e c k l i s t d i v e r i f i c a d e i r e q u i s i t i m i n i m i d e l b a n i s c r i t t o a l l ’ Or d i n e d e i Do t t o r i Co m m e r c i a l i s t i e d E
i n p o s s e s s o d e i r e q u i s i t i r i c h i e s t i d a l l a Di r e t t i v a d e l 16 a p r i l e 2014 , c h e m o d i f i c a l a d i r e t t i v a 2006/43/CE r e l a t
e d e i c o n t i c o n s o l i d a t i , e d a l l a r e l a t i v a l e g i s l a l a r e g o l a r i t à a m m i n i s t r a t i v o -c o n t a b i l e d e l l e s p e s c o n f o r m i t à a l l a n o r m a t i v a d i r i f e r i m e n t o v i g e e d i t u t t i i r e q u i s i t i p r e v i s t i d a l l ’ Av v i s o e d a l l a n a z i o n a l i e d e u r o p e e i n m a t e r i a e l a c o n g r u e n z a c o n l
3. Tu t t a l a s o p r a r i c h i a m a t a d o c u m e n t a z i o n e d e v e e s s e r d e l l a r i c e r c a e i l s i s t e m a i n f o r m a t i c o “ Re Gi S” e s e c o d i m o n i t o r a g g i o e c o n o m i c o e u t i l i z z a n d o c o n g i u n t a d e l l a r i c e r c a , a d i s p o s i z i o n e d e i d e s t i n a t a r i i s t i t
t r a m i t e p o s t a e l e t t r o n i c a c e r t i f i c a t a (PEC) d a p a r t e d
4. La d o c u m e n t a z i o n e d i s u p p o r t o d e v e e s s e r e a d i s p o s i z v e r i f i c a d e l PNRR, p r e s s o i l So g g e t t o a t t u a t o r e /b e n e c u s t o d i a .
5. La Di r e z i o n e g e n e r a l e d e l l a Ri c e r c a e d i n n o v a z i o n e i a p p l i c a r e u n a d e c u r t a z i o n e p a r i a l 10% d e l l a r a t a d e l 1 d e l p r e s e n t e a r t i c o l o s i a t r a s m e s s a a l Mi n i s t e r o q u a r a n t e s i m o g i o r n o d a l l a d a t a d i c o n c l u s i o n e d e l p
6. Il Mi n i s t e r o p r o v v e d e a d a p p l i c a r e u n a d e c u r t a z i o n d o c u m e n t a z i o n e d i c u i a l c o m m a 1 d e l p r e s e n t e a r t i c c o m p r e s o t r a i l q u a r a n t u n e s i m o e i l c i n q u a n t e s i m o g
7. Il Mi n i s t e r o , p r e v i a c o m u n i c a z i o n e p r e v e n t i v a a l So g p e r l a s o s p e n s i o n e d e l f i n a n z i a m e n t o e l a c o n s e g u e r e c u p e r o d i t u t t e d e l l e s o m m e g i à e r o g a t e , a n c h e q u e l g r u p p o d e l l a r i c e r c a , c o m p r e n s i v e d e g l i i n t e r e s s i l c o m m a 1 d e l p r e s e n t e a r t i c o l o n o n s i a t r a s m e s s a a l Mi d i c o n c l u s i o n e d e l p r o g e t t o .
8. Il Mi n i s t e r o s i r i s e r v a l a f a c o l t à d i c h i e d e r e i n f o r So g g e t t o a t t u a t o r e /b e n e f i c i a r i o , c h e d e v e f o r n i r e r q u a l o r a :
- l a r e l a z i o n e f i n a l e n o n s i a c o n s i d e r a t a i d o n e a a i n c o n f o r m i t à a q u a n t o p r e v i s t o n e l p r o g e t t o e n e
- l a r e n d i c o n t a z i o n e r i s u l t i i n c o m p l e t a o i n c o n g r
9. Il Mi n i s t e r o p r o v v e d e r à a d e m e t t e r e l a v a l u t a z i o n e c a s o d i m a n c a t o o e s a u s t i v o r i s c o n t r o d a p a r t e d e l So a l p r e c e d e n t e c o m m a , i l Mi n i s t e r o c o m u n i c a a l So g g e t
o r d i n e a l l a r e l a z i o n e f i n a l e e c o n s e g u e n t e m e n t e i n c h i e d e r e l a r e s t i t u z i o n e d e l l e s o m m e g i à e r o g a t e , c o d i m a n c a t o r i s c o n t r o o p p u r e l a d d o v e d a l l ’ i s t r u t t o r s t a t i d i s a t t e s i g l i o b i e t t i v i d i c u i a l p r o g e t t o
10. Il Mi n i s t e r o , p r e v i a c o m u n i c a z i o n e p r e v e n t i v a a l So g Co m i t a t o t e c n i c o s a n i t a r i o s e z . c ) u n d o s s i e r , q u a l o r m i n i s t e r i a l e , n o n c o n s e n t a d i e s p r i m e r e u n c o m p i u t Co m i t a t o è v i n c o l a n t e p e r i l So g g e t t o b e n e f i c i a r i o a
Ar t . 9 Ve r i f i c a f i n a n z i a r i a p r e v e n t i v a Il So g g e t t o a t t u a t o r e -b e n e f i c i a r i o , a l f i n e d e l l ’ e r Mi n i s t e r o d e l l a s a l u t e – Un i t à d i m i s s i o n e p e r l ’ a t t s i s t e m a “ Re Gi S” l a r e n d i c o n t a z i o n e e c o n o m i c a c o r r e
a l c o m m a 2 d e l l ’ a r t i c o l o 8 d e l l a p r e s e n t e c o n v e n z i o n d i s o g g e t t i q u a l i f i c a t i a l l ’ Au d i t a l i v e l l o e u r o p e a l a c o m p l e t e z z a d e l l a d o c u m e n t a z i o n e i n b a s e a l l e d i q u e l l e e u r o p e e
Ar t . 10 Pr o c e d u r a d i p a g a m e n t o a l So g g e t t o b e n e
1. Le p r o c e d u r e d i e r o g a z i o n e d e i f o n d i s u r i c h i e s t a d a n t i c i p a z i o n e e a t i t o l o d i r i m b o r s o a l l ’ Un i t à d i
s p e c i f i c h e m o d a l i t à i n c o n f o r m i t à c o n q u a n t o i n d i c
- m a s s i m o 40% a l m o m e n t o d e l l a c o m u n i c a z i o n e , d a p a r
d e l l ’ a t t i v i t à d i r i c e r c a , a t i t o l o d i a n t i c i p a z i o
- q u o t a a r i m b o r s o p e r u n u l t e r i o r e p e r m a s s i m o u n 12° m e s e d a l l ’ i n i z i o d e l l e a t t i v i t à p r o g e t t u a l i , r e l a z i o n e s c i e n t i f i c a i n t e r m e d i a e d o p o l a s u a a p r i c h i e s t e d i p a g a m e n t o a t i t o l o d i r i m b o r s o p e r l b e n e f i c i a r i o , c o m e r i s u l t a n t i d a l s i s t e m a i n f o r
l e g g e 30 d i x x x x x x 0000, x , 000.
- q u o t a a r i m b o r s o r e s i d u a l e a s a l d o , a c o n c l u s i o n So g g e t t o a t t u a t o r e /b e n e f i c i a r i o d e l l a r e l a z i o n e c o n o m i c a , s u l l a b a s e d e l l a p r e s e n t a z i o n e d e l l a c o n c l u s i o n e d e l p r o g e t t o , i n c o e r e n z a c o n l e r i s a l l ’ a r t i c o l o 1, c o m m a 1043, d e l l a l e g g e 30 d i c e m b r e 2020
2. A g a r a n z i a d e l l a c o e r e n z a c o n l ’ i n i z i o d e l l ’ a t t i v i i m p e g n a a d a n t i c i p a r e l e r i s o r s e e c o n o m i c h e n e c e c o r r i s p o n d e r s i d a p a r t e d e l Mi n i s t e r o s i a n o i n r e g i
3. La d d o v e n o n v e n g a n o r i s p e t t a t i i t e r m i n i d i c u i a l l t e m p e s t i v a e r o g a z i o n e d e i f o n d i , i l So g g e t t o a t t u a t r e s p o n s a b i l i t à p e r e v e n t u a l i r i t a r d i n e l l ’ e r o g a z i
4. Al t e r m i n e d e l l e v e r i f i c h e l a Di r e z i o n e g e n e r a l e d e d e l l a Sa l u t e c o m u n i c h e r à d a l l ’ Un i t à d i m i s s di eo ln e p e
Mi n i s t e lr
eo rSai
ls uu lt
te a n z e d e l l e v e r i f i c h e p e r c o n s e n t i
p a g a m e n t i .
Ar t . 11 Va r i a z i o n i d e l p r o g e t t o e d e l p i a n o d e i
1. A p a r t i r e d a l 3° m e s e s u c c e s s i v o a l l ’ a v v i o d e l p r o g e p r o g e t t o , i l So g g e t t o a t t u a t o r e -b e n e f i c i a r i o , c o n n o Pr i n c i p a l In v e s t i g a t o r , t r a s m e s s a t r a m i t e i l p o r t a l “ Re Gi S” , p u ò p r o p o r r e v a r i a z i o n i a l p r o g e t t o , c o e r e n t
d i f o n d i t r a l e u n i t à o p e r a t i v e , p u r c h é n o n c o m p o r t i c a r i c o d e l Mi n i s t e r o , c h e d o v r a n n o e s s e r e a c c o l t e c o d i m o d i f i c a d e v e d i m o s t r a r e l e n e c e s s i t à s c i e n t i f i m o d i f i c a p r o p o s t a r i s p e t t o a l r a g g i u n g i m e n t o d e g l e f f i c a c i a s o l o d o p o l ’ a p p r o v a z i o n e d a p a r t e d e l Mi n p i a n o d e i c o s t i p e r i l CUP Ma s t e r e p e r i CUP d e l l e s i n g a t t u a t o r e -b e n e f i c i a r i o .
2. No n è c o n s e n t i t o a l d i f u o r i d e l p e r i o d o d i c u i a l c o m e v e n t u a l e n e c e s s i t à d i u n ’ u l t e r i o r e m o d i f i c a p r o g e s o l o d o p o 3 m e s i d a l l ’ a p p r o v a z i o n e d a p a r t e d e l Mi n i s t i p o l o g i a o v v e r o s i a s c i e n t i f i c a o e c o n o m i c a .
3. Il p i a n o d e i c o s t i , r i p o r t a t o n e l l a p r o p o s t a p r o g e t t t o t a l e d e l f i n a n z i a m e n t o a s s e g n a t o e a l r i p a r t o i n i i n d i c a t i v o p e r q u a n t o r i g u a r d a l a r i p a r t i z i o n e t r a d i t a l i c o s t i .
4. La d i s t r i b u z i o n e d e l l e s o m m e t r a l e d i v e r s e v o c i d i c è c o n s e n t i t a s o t t o l a r e s p o n s a b i l i t à d e l So g g e t t o a c h e d o v r à v e r i f i c a r e i l r i s p e t t o d e l l e p e r c e n t u a l i
5. Qu a l s i a s i p r o p o s t a e m e n d a t i v a d e v e e s s e r e a d e g u a t d o c u m e n t a r e c h e q u a n t o r i c h i e s t o r i s u l t i i n d i s p e n s a s u o t e m p o p r e f i s s a t i .
6. So l o d o p o l ’ a p p r o v a z i o n e d e l Mi n i s t e r o , i l s o g g e t a l l ’ a p p l i c a z i o n e d e l l e m o d i f i c h e d i c u i a l c o m m a
i n a d e m p i m e n t i a l p r e s e n t e a r t i c o l o i l Mi n i s t e r o h c o n v e n z i o n e , d a n d o n e c o m u n i c a z i o n e a l So g g e t t o a t t f i n a n z i a m e n t o , n o n c h é a l r e c u p e r o d i t u t t o l ’ i m p o r t
Ar t . 12 Pr o r o g a
1. Il t e r m i n e d e l l a r i c e r c a p u ò e s s e r e p r o r o g a t o d a l Mi n d i s c a d e n z a o r i g i n a l e , s o l o a s e g u i t o d i f o r m a l e , m o t d a l l e g a l e r a p p r e s e n t a n t e d e l So g g e t t o a t t u a t o r e -b t r a m i t e i l p o r t a l e Wo r k f l o w d e l l a r i c e r c a .
2. La r i c h i e s t a d i c u i a l c o m m a 1 p u ò e s s e r e a v a n z a t a s o l o t e r m i n e o v v e r o s i a d o p o 12 m e s i d a l l ’ a v v i o p r o g e t t o e c o n f o r m a l e e m o t i v a t a i s t a n z a d a p a r t e d e l So g g e t t o
c h e d i m o s t r i l e n e c e s s i t à s c i e n t i f i c h e a l l a b a s e r a g g i u n g i m e n t o d e g l i o b i e t t i v i p r o g e t t u a l i p r e v i s d e l Mi n i s t e r o .
Ar t . 13 Pr o p r i e t à e d i f f u s i o n e d e i r i s u l t a t
1. La p r o p r i e t à d e g l i s t u d i , d e i p r o d o t t i e d e l l e m e t o r e g o l a m e n t a t a d a l l a n o r m a t i v a v i g e n t e i n m a t e r i a , f i r m a t a r i e d e l p r e s e n t e a t t o , f e r m a r e s t a n d o l a p o s s Na z i o n a l e d i f r u i r n e , p r e v i a r i c h i e s t a a l l e p a r t i f i
2. Ne l c a s o i n c u i i l So g g e t t o a t t u a t o r e /b e n e f i c i a r i o i a n c h e p a r z i a l e , r e l a t i v o a l l a r i c e r c a i n q u e s t i o n e , a d e v e d a r n e p r e v e n t i v a c o m u n i c a z i o n e a l Mi n i s t e r o .
3. Il So g g e t t o a t t u a t o r e /b e n e f i c i a r i o s i i m p e g n a a g a r p r o g e t t o , a n c h e o n l i n e , s i a s u l w e b c h e s u i s o c i a l m e d
4. Qu a l s i a s i d o c u m e n t o p r o d o t t o , i v i c o m p r e s e l e p u b b l i o g g e t t o d e l l a p r e s e n t e c o n v e n z i o n e – p e r i q u a l i d e Mi n i s t e r o - d e v e c o n t e n e r e l ’ i n d i c a z i o n e c h e i l p r o u n ’ e s p l i c i t a d i c h i a r a z i o n e c h e r e c i t i "f i n a n z i a t o M6C2 - In v e s t i m e n t o 2.1 Va l o r i z z a z i o n e e p o t e n z i a m e n t
l ’ e m b l e m a d e l l ’ Un i o n e Eu r o p e a e d i l c o d i c e d e l p r o g e
5. I p r o d o t t i d i c u i a l p r e c e d e n t e c o m m a 4 d e v o n o e s s e r e r l ’ i m m e d i a t a f r u i z i o n e d a p a r t e d e l p u b b l i c o (a d e s e
d i p u b b l i c a z i o n e s c i e n t i f i c a p e r l a q u a l e s i a n e c e s p a g a m e n t o p e r l a c o n s u l t a z i o n e r e l a t i v a L’ e v e n t u a l s o l a p u b b l i c a z i o n e , s a r à o g g e t t o d i u n a p e n a l e p a r i a
6. Il Mi n i s t e r o n o n r i c o n o s c e l ’ e l e g g i b i l i t à d e i c o s t i p u b b l i c a z i o n i n o n s i f a c c i a e s p r e s s a m e n z i o n e d e l f c o d i c e p r o g e t t o .
7. Le p a r t i c o n v e n g o n o c h e i l Mi n i s t e r o p o s s a d a r e d i r e s i t o w e b , d e l l ’ e s t r a t t o d e l l a p r o p o s t a p r o g e t t u a l e s i n t e t i c a e d e l l e p u b b l i c a z i o n i s c i e n t i f i c h e d a e s
Ar t . 14 Ca s i d i r i d u z i o n e , s o s p e n s i o n e o r e v o c a d
a | . | m o d i | f | i | c h e i n g i u s t i f i c a t e a l l a c o m p o s i z i o n e d e l |
b | . | m a n c | a | t | o r i s p e t t o d e i v i n c o l i p r e v i s t i d a l l ’ Av v i |
c | . | m a n c | a | t | o r i s p e t t o d e g l i o b b l i g h i d i c u i a l l ’ a r t . 5 |
d | . | m a n c | a | t | o r a g g i u n g i m e n t o , n e i t e m p i a s s e g n a t i , d e |
s v o l | g | i | m e n t o d e l p r o g e t t o ; | ||
e | . | m a n c | a | t | a o r i t a r d a t a p r e s e n t a z i o n e d e l l a r e l a z i |
r i c e | r | c | a ; | ||
f | . | m a n c | a | t | a o r i t a r d a t a p r e s e n t a z i o n e - o l t r e i l c i n q |
p r o g | e | t | t o - d e l l a r e l a z i o n e f i n a l e d e l l a r i c e r c a e | ||
i f o n | d | i | m i n i s t e r i a l i ; | ||
g | . | m o d i | f | i | c h e d e l p r o g e t t o o v a r i a z i o n i n e l l a d i s t r |
a u t o | r | i | z z a t e ; |
1. Il Mi n i s t e r o p r o c e d e a d i c h i a r a r e l a s o s p e n s i o n e o r e c o n c o n s e g u e n t e e v e n t u a l e r e s t i t u z i o n e d e l l e s o m m m a t u r a t i , n e i s e g u e n t i c a s i :
2. Il Mi n i s t e r o a p p l i c a r i d u z i o n i f i n a n z i a r i e i n m i r i c o n o s c i m e n t o d e l l e s p e s e n e i s e g u e n t i c a s i :
a . m a n c a t o r i s p e t t o d e i c r i t e r i d i a m m i s s i b i l i t à d m a s s i m a l i p r e v i s t i p e r a l c u n e c a t e g o r i e d i s p p u b b l i c a z i o n i i n c u i n o n s i f a c c i a e s p r e s s a m e n z d e l PNRR e d e l c o d i c e p r o g e t t o ;
b . r i d u z i o n e f i n a n z i a r i a n e l l a m i s u r a d e l 5% d e l l a a t t u a t o r e /b e n e f i c i a r i o a l t e r m i n e d e l l e a t t i v i
c . r | i | d u | z | i | o | n e f i n a n z i a r i a n e l l a m i s u r a d e l 10% d e l l a |
r | i | c e | r | c | a | e l a r e n d i c o n t a z i o n e d e l l e s p e s e s o s t e n |
c | o | m p | r | e | s | o t r a i l t r e n t u n e s i m o e i l q u a r a n t e s i m o g |
d . r | i | d u | z | i | o | n e f i n a n z i a r i a n e l l a m i s u r a d e l 20% d e l l a |
r | i | c e | r | c | a | e l a r e n d i c o n t a z i o n e d e l l e s p e s e s o s t e n |
c | o | m p | r | e | s | o t r a i l q u a r a n t u n e s i m o e i l c i n q u a n t e s |
e f | . . | p r a r f r a p r p | r i t i i i t u e u | o d t v n d t b p b | g u u i a u u b o b | e t t o ; z i o n e f i n a n z i a r i a n e l l a m i s u r a d e l 5% d e l l ’ i a t o r e /b e n e f i c i a r i o a l t e r m i n e d e l l e a t t i v i s t e i m p a t t a t e a s e g u i t o d e l l o s v o l g i m e n t n z i a m e n t o o t t e n u t o n e l l ’ a m b i t o d e l PNRR e d e l z i o n e f i n a n z i a r i a n e l l a m i s u r a d e l 10% d e l l ’ i a t o r e /b e n e f i c i a r i o a l t e r m i n e d e l l e a t t i v l i c a t i s u r i v i s t e i m p a t t a t e a s e g u i t o d e l l o sp iu tb ob rl yi c o d o v e s o n o r e s i d i s p o n i b i l i i d a t i g l i c a z i o n i s c i e n t i f i c h e c o r r e l a t e . |
r i v i s t e i m p a t t a t e a s e g u i t o d e l l o s v o l g i m e n t o d p u b b l i c a z i o n i p r o d o t t e r e c a n o l a m e n z i o n e d e l f e d e l c o d i c e p r o g e t t o ;
Ar t . 15 Ri s o l u z i o n e d i c o n t r o x x x x x x
0. Xx r q u a l s i a s i c o n t r o v e r s i a , i l So g g e t t o a t t u a t o r e -b e g e n e r a l e d e l l a r i c e r c a e d e l l ’ i n n o v a z i o n e i n s a n i t e v e n t u a l i p r o b l e m a t i c h e a l p a r e r e d i c o m p e t e n z a d e l i l Mi n i s t e r o . Le p a r t i , c o n l a s o t t o s c r i z i o n e d e l l a p r c h e s a r à e s p r e s s o d a l Co m i t a t o t e c n i c o s a n i t a r i o (C s c i e n t i f i c a d e l p r o g e t t o e l e e v e n t u a l i r i c a d u t e e c
2. Co n l a f i r m a d e l l a p r e s e n t e c o n v e n z i o n e i l Pr i n c i p a l c o m m a 1.
3. Qu a l o r a a s e g u i t o d e l l a v a l u t a z i o n e d e l CTS, d i c u i a c o n t r o v e r s i e , d i v e r s e d a q u e l l e d e l c o m m a 1, c h e d o v e s c o m p e t e n t e è i l Fo r o d i Ro m a .
Ar t . 16 Ri s o l u z i o n e p e r i n a d e m p i m e n t o
1. Il Mi n i s t e r o p o t r à a v v a l e r s i d e l l a f a c o l t à d i r i s o l a t t u a t o r e /b e n e f i c i a r i o n o n r i s p e t t i g l i o b b l i g h i
l ’ a s s o l v i m e n t o d a p a r t e d e l l o s t e s s o Mi n i s t e r o d e g l
Ar t . 17 Di r i t t o d i r e c e s s o
1. Il Mi n i s t e r o p o t r à r e c e d e r e i n q u a l u n q u e m o m e n t o d a g n e i c o n f r o n t i d e l So g g e t t o a t t u a t o r e /b e n e f i c i a r i o q d e l l e a t t i v i t à , i n t e r v e n g a n o f a t t i o p r o v v e d i m e n t i
s t i p u l a d e l l a p r e s e n t e Co n v e n z i o n e o n e r e n d a n o i m p
Ar t . 18 Co m u n i c a z i o n i e s c a m b i o d i i n f o r m a z i o
1. Ai f i n i d e l l a d i g i t a l i z z a z i o n e d e l l ’ i n t e r o c i c l o Mi n i s t e r o d e l l a s a l u t e d e v o n o a v v e n i r e a t t r a v e r s o i Wo r k f l o w d e l l a r i c e r c a , a d i s p o s i z i o n e d e l So g g e t t a t t r a v e r s o i l s i s t e m a m e s s o a d i s p o s i z i o n e d a l Mi “ Re Gi S” .
2. Il So g g e t t o a t t u a t o r e /b e n e f i c i a r i o a t t r a v e r s o i l p In v e s t i g a t o r d e v o n o f i r m a r e d i g i t a l m e n t e t u t t i g l i
Ar t . 19 Tr a c c i a b i l i t à d e i f l u s s i f i n a n z i a r
1. Le p a r t i s i i m p e g n a n o a l l ’ o s s e r v a n z a , p e r q u a n t o d i r a l l a t r a c c i a b i l i t à d e i f l u s s i f i n a n z i a r i d i c u i a l l
Ar t . 20 Pr o t e z i o n e d e i d a t i p e r s o n a l i
1. Ne l c o r s o d e l l ’ e s e c u z i o n e d e l l e a t t i v i t à o g g e t t o d e t r o v a r s i n e l l a c o n d i z i o n e d i d o v e r t r a t t a r e d a t i
d e l l ’ a l t r a Pa r t e , m o t i v o p e r c u i l e s t e s s e s i i m p e g n a p e r s o n a l i i n c o n f o r m i t à a l l e d i s p o s i z i o n i d i c u i a l
e d e l Co n s i g l i o , d e l 27 a p r i l e 2016, r e l a t i v o a l l a p r o t e t r a t t a m e n t o d e i d a t i p e r s o n a l i , n o n c h é a l l a l i b e r a 95/46/CE (Re g o l a m e n t o g e n e r a l e s u l l a p r o t e z i o n e d e i d a t a d e g u a m e n t o .
2. Le Pa r t i s i i m p e g n a n o a c o n d u r r e l e s u d d e t t e a t t i v i c o r r e t t e z z a , l i c e i t à , t r a s p a r e n z a e t u t e l a d e l l a r i e s c l u s i v o f i n e d i p e r s e g u i r e l e f i n a l i t à d i c u i a l l a d i l e g g e a l l o s t e s s o c o n n e s s i . Ta l i d a t i s a r a n n o t r a t
- a d o p e r a d i p r o p r i d i p e n d e n t i e /o c o l l a b o r a t o r i c h h a n n o l a n e c e s s i t à d i t r a t t a r l i , p e r l e s o l e f i n a l i n e c e s s a r i o a l l o r o c o n s e g u i m e n t o .
Ar t . 21 Ef f i c a c i a
1. La p r e s e n t e c o n v e n z i o n e , v i n c o l a n t e a l l 'a t t o d e l l a s e i l Pr i n c i p a l In v e s t i g a t o r , d i v e n t e r à e f f i c a c e p e r d e g l i o r g a n i d i c o n t r o l l o .
Ar t . 22 Di s p o s i z i o n i Fi n a l i
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Ro m a , (d a t a d e l l a s o t t o s c r i z i o n e c o m e q u e l l a d e l l ’ u l t i
p e r i l Mi n i s t e r o d e l l a s a l u t e
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1 - General information
Project code: PNRR-MAD-2022-12375670
PI / Coordinator: XXXXX XXXXXX
Project topic: C2) Malattie croniche non trasmissibili, ad alto impatto sui sistemi sanitari e socio-assistenziali: eziopatogenesi e meccanismi di malattia
Applicant Institution: Istituti fisioterapici ospitalieri - Istituto Regina Elena
Call section: Proposal title:
Malattie Croniche non Trasmissibili (MCnT) ad alto impatto sui sistemi sanitari e socio-assistenziali
Addressing liver fibrosis prevention and treatment: an unbiased query on the hepatic microenvironment with a perspective targeting of the pro-fibrotic kinase HIPK2
Duration in months: 24
MDC primary: Gastroenterologia
MDC secondary: Oncologia
Project Classification IRG: Project Classification SS:
Oncology 1 - Basic Translational Tumor Microenvironment - TME
Project Keyword 1:
Molecular and cellular aspects of bi-directional interaction between tumor and stromal cells (including fibroblasts, glial cells, epithelial cells, adipocytes, immune cells, inflammatory cells, vascular compartments, and bone marrow cells) during neoplastic progression, tumor angiogenesis, growth and metastasis, including studies of cancer stem cell niche and tumor cell dormancy
X
Project Request: Animals:
Project total financing request to the MOH: € 1.000.000
Humans:
Clinical trial:
X
Free keywords: Liver Fibrosis; HIPK2; organotypic slice culture system; HIPK2 inhibition by abemaciclib
Declarations
In case of a Synergy grant application 'Principal Investigator'(PI) means 'corresponding Principal Investigator on behalf of all Principal Investigators', and 'Host Institution' means 'corresponding Host Institution'.
1) The Principal Investigator declares to have the written consent of all participants on their participation and on the content of this proposal, as well as of any researcher mentioned in the proposal as participating in the project (either as other PI, team member or collaborator). | X |
2) The Principal Investigator declares that the information contained in this proposal is correct and complete. | X |
3) The Principal Investigator declares that all parts of this proposal comply with ethical principles (including the highest standards of research integrity — as set out, for instance, in the European Code of Conduct for Research Integrity — and including, in particular, avoiding fabrication, falsification, plagiarism or other research misconduct). | X |
4) The Principal Investigator is only responsible for the correctness of the information relating to his/her own organisation. Each applicant remains responsible for the correctness of the information related to him and declared above. | X |
Personal data protection
The assessment of your grant application will involve the collection and processing of personal data (such as your name, address and CV), which will be performed pursuant to Regulation (EC) No 45/2001 on the protection of individuals with regard to the processing of personal data by the Community institutions and bodies and on the free movement of such data. Unless indicated otherwise, your replies to the questions in this form and any personal data requested are required to assess your grant application in accordance with the specifications of the call for proposals and will be processed solely for that purpose. Details concerning the purposes and means of the processing of your personal data as well as information on how to exercise your rights are available in the privacy statement. Applicants may lodge a complaint about the processing of their personal data with the European Data Protection Supervisor at any time.
Abstract
Liver fibrosis is a major cause of morbidity and mortality from chronic liver diseases. The development of fibrosis is a common pathological consequence of a variety of chronic stimuli, including autoimmune, drug- and alcoholic-induced, cholestatic and metabolic diseases. Fibrosis is the first step toward the progression to cirrhosis and eventually to hepatocellular carcinoma while it is still controversial whether it also establishes a metastasis-permissive liver. Currently, there are no non-invasive, cost-effective, and clear biomarkers able to predict either progression or effective therapies for liver fibrosis.
Fibrosis is characterized by excessive synthesis, deposition, and contraction of extracellular matrix components produced mostly by myofibroblasts. In the pathogenesis of liver fibrosis, a key role is played by the hepatic stellate cells (HSCs) that are the main source of extracellular matrix. Following chronic liver injury, quiescent HSCs are exposed to pro-fibrogenic factors and activated toward a myofibroblast phenotype. Therefore, inhibition of HSC activation is a possible target to attenuate liver fibrosis.
Homeodomain-Interacting Protein Kinase 2 (HIPK2) is an evolutionarily conserved kinase which acts as a co-regulator of several transcription factors and modulates different cellular processes such as proliferation, morphogenesis, and cell death. HIPK2 contributes to numerous signaling pathways, including those primarily involved in fibrosis, such as TGF-beta/SMAD and WNT/beta-catenin. A direct role for HIPK2 in fibrosis was first identified in a model for human HIV-associated nephropathy through a systems biology approach that takes into account protein-protein and protein-DNA interactions.
Following this initial study in kidney fibrosis, HIPK2 has been identified as a regulator of signaling pathways activated in lung fibrosis, fibrotic keloid formation, and pro-fibrogenic response of HSCs in liver fibrosis. In addition, specific HIPK2 small molecule inhibitors have been designed and produced and HIPK2 has been proposed as a new druggable target for anti- fibrosis therapy.
Traditional preclinical platforms to explore physio-pathological processes and develop new therapeutic approaches, including 2D cell lines, 3D organoid cell cultures and their xenografts, have limitations in evaluating the contribution of stromal and immune microenvironment. Genetically engineered mouse models (GEMMs) provide unique mechanistic insights related to genetic and pharmacologic interventions. However, for a faithfully recapitulation of human diseases, the use of GEMMs should be integrated with human models. Recently, an organotypic slice culture technique has been developed and standardized. These sliced tissues can be maintained in culture for at least one week, have the advantage of maintaining the morphology and microenvironment of the host tissue, and allow the investigation of spatial dynamics, drug delivery, and stromal and immune responses.
Here, we propose to address prevention and treatment of liver fibrosis with an unbiased query of the hepatic microenvironment performed on human liver slice cultures (hLSCs) and by targeting the pro-fibrotic kinase HIPK2 both in liver-specific GEMM and in hLSCs. This proposal has a high likelihood of identifying novel biomarker(s) for liver fibrosis progression and treatment.
Yes
In order to best review your application, do you agree that the above non-confidential proposal title and abstract can be used, without disclosing your identity, when contacting potential reviewers?
2 - Participants & contacts
Operative Units | |||||
Institution that perform as UO | CF Institution | Department / Division / Laboratory | Role in the project | Southern Italy | SSN |
1 - Istituti fisioterapici ospitalieri - Istituto Regina Xxxxx | 02153140583 | Research and Advanced Technologies/Unit of Cellular Networks and Molecular Therapeutic Targets | Project management, mouse model, liver samples, cell biology and data analysis | X | |
2 - University of Xxxxxx Xxxxxxxx XX | 00876220633 | Molecular Medicine and Medical Biotechnology/Genomic Facility | OMICs and data analyses | X | |
3 - Istituto Nazionale Tumori IRCCS Fondazione X. Xxxxxxx | 00911350635 | Division of Abdominal Oncology | Patients' selection, liver samples and clinical data | X | X |
4 - Verona University Hospital Trust (AOUI Verona) | 03901420236 | Department of Medicine/Section of Oncology | Clinical and model data analyses | X | |
Principal Research Collaborators | ||
Key Personnel Name | Operative Unit | Role in the project |
1 - Piaggio Giulia | Istituti fisioterapici ospitalieri - Istituto Regina Xxxxx | XxXX |
2 - XXXXX XXXX XXXX | Xxxxxxxx fisioterapici ospitalieri - Istituto Regina Elena | Additional collaborator UO1 |
3 - Xxxxx Xxxxxxxx | University of Xxxxxx Xxxxxxxx XX | Head of UO2 |
4 - xxxxx xxxxxxxxx | Istituto Nazionale Tumori IRCCS Fondazione X. Xxxxxxx | Head of UO3 |
5 - XXXXXXX XXXXXXX | Verona University Hospital Trust (AOUI Verona) | Head of UO4 |
6 Under 40 - XXXXXXX XXXXXX | Xxxxxxxx fisioterapici ospitalieri - Istituto Regina Elena | Additional collaborator UO1 |
7 Under 40 - Xxxxxxxx Xxxxxx | Xxxxxxxx fisioterapici ospitalieri - Istituto Regina Elena | Additional collaborator UO1 |
Key Personnel Name | Co-PI | Resp. CE | Resp. Animal | Birth Date | Gender |
1 - Piaggio Giulia | X | X | 09/05/1962 | F | |
2 - XXXXX XXXX XXXX | 12/08/1961 | M | |||
3 - Xxxxx Xxxxxxxx | 10/05/1970 | M | |||
4 - xxxxx xxxxxxxxx | 29/08/1964 | M | |||
5 - XXXXXXX XXXXXXX | 01/03/1968 | M | |||
6 Under 40 - XXXXXXX XXXXXX | 08/05/1984 | M | |||
7 Under 40 - Xxxxxxxx Xxxxxx | 10/03/1987 | M |
Responsible who requests CE authorization: XXXXX XXXXXX
Additional research collaborators under 40 to hire | ||||||
Key Personnel Name | Operative Unit | Birth Date | Gender | Role in the project | Degree | Actual Pos. and Inst. |
0 - Xxxxx Xxxxxxxxx Xxxxx | University of Xxxxxx Xxxxxxxx | 21/11/1990 | F | Under40 to hire | Master Degree in | Laboratory |
II | Sanitary Biology | technician at | ||||
IRCCS Casa | ||||||
Sollievo della | ||||||
Sofferenza | ||||||
1 - Xxxxxxxxx Xxxxxxxx | University of Xxxxxx Xxxxxxxx | 06/12/1995 | F | Under40 to hire | Master degree in | Research |
II | Medical and | collaborator at | ||||
Pharmaceutical | IRCCS Casa | |||||
Biotechnology | Sollievo della | |||||
Sofferenza | ||||||
2.1 Administrative data of participating
Operative Unit Number 1:
Address: Xxx Xxxx Xxxxxxxx 00, 00000 Xxxx, Xxxxx
PEC: xxxxx.xxxxxx@xxxxxxxxxxxx.xx
Operative Unit Number 2:
Address: Xxxxx Xxxxxxx X 00, 00000 Xxxxxx, Xxxxx
PEC: xxxxxxxx.xxxxx@xxxxxxxxxxxx.xxxxx.xx
Operative Unit Number 3:
Address: Xxx Xxxxxxx Xxxxxxx 00, 00000 Xxxxxx, Xxxxx
PEC: xxxxxxxxxxxxxxxxxx@xxx.xxxxxxxxxxxxxx.xx.xx
Operative Unit Number 4:
Address: Xxxxxxxx Xxxxxxxx Xxxxxxx 0, 00000 Xxxxxx, Xxxxx
Operative Unit Number 5 (self financing):
Address: n/a
PEC: n/a
2.2 Principal Investigator (PI) Profile
Last Name: XXXXX
First Name: XXXXXX
Last name at birth: XXXXX
Gender: F
Title: Principal investigator Nationality: italianaa Date of birth: 26/02/1961
Official H index (Scopus or Web of Science): 40.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Roma
Scopus Author Id:7003339359 ORCID ID:0000-0001-8526-0044 RESEARCH ID:ABH-6774-2020
Contact address
Current organisation name: Istituti fisioterapici ospitalieri - Istituto Regina Elena
Current Department / Faculty / Institute / Laboratory name: Research and Advanced Technologies/Unit of Cellular
Networks and Molecular Therapeutic Targets
Street: Xxx Xxxx Xxxxxxxx 00
Postcode / Cedex: 00144 Town: Roma
Phone:x000000000000 Phone 2: 0000000000
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Università degli Studi di Roma "Sapienza" Rome, Italy | Single-cycle master's degree / Laurea magistrale a ciclo unico | Medical Doctor in Medicine and Surgery | 1981 | 1987 |
Università degli Studi di Roma "Sapienza" Rome, Italy | Specialization / Specializzazione | Allergy and Clinical Immunology | 1987 | 1990 |
Università degli Studi di Roma "Sapienza" Rome, Italy | PhD | Endocrinology and Metabolism | 1994 | 1997 |
Personal Statement:
Expert of cellular and molecular mechanisms of tumorigenicity and tumor-cell response therapies. She has developed several cellular and molecular biology techniques in order to characterize complex molecular mechanisms related to neoplastic transformation, differentiation and response to genotoxic-stresses. With the co-PI, she has performed seminal and largely cited studies on the p53 activator HIPK2. She will be responsible for the management of the project
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
Università degli Studi di Roma "Sapienza" Rome, Italy | Department of Allergy and Clinical Immunology Policlinico Umberto I | Xxxxx xxxx'Xxxxxxxxxx, 00000 Xxxx, Xxxxx | Internal student | 1983 | 1987 |
National Institutes of Health (NIH) | Laboratory of Immunopathology, Institute of Allergy and Infectious Diseases | 0000 Xxxxxxxxx Xx Xxxxxxxx, Xxxxxxxx 00000, XXX | Postdoctoral training (Xxxxxxx fellow) | 1988 | 1991 |
Istituti Fisioterapici Ospitalieri (IFO) - Regina Elena National Cancer Institute - IRCCS | Department of Experimental Oncology - Molecular Oncogenesis Laboratory | Xxx xxxxx Xxxxx x'Xxx 000 - 00000 Xxxx, Xxxxx | AIRC Fellow | 1991 | 1993 |
Istituti Fisioterapici Ospitalieri (IFO) - Regina Elena National Cancer Institute - IRCCS | Department of Experimental Oncology - Molecular Oncogenesis Laboratory | Xxx xxxxx Xxxxx x'Xxx 000 - 00000 Xxxx, Xxxxx | Senior scientist | 1996 | 1998 |
Istituti Fisioterapici Ospitalieri (IFO) - Regina Elena National Cancer Institute - IRCCS | Department of Experimental Oncology - Molecular Oncogenesis Laboratory | Xxx xxxxx Xxxxx x'Xxx 000 - 00000 Xxxx, Xxxxx | PI New Unit Start-Up Grant from AIRC | 1998 | 2002 |
Istituti Fisioterapici Ospitalieri (IFO) - Xxxxxx Xxxxx National Cancer Institute - IRCCS | Department of Research and Advanced Diagnostic and Technological Innovation Translational Research Area | Xxx Xxxx Xxxxxxxx 00 - 00000 Xxxx, Xxxxx | Stuff scientist (Dirigente medico) | 2002 | 2016 |
Istituti Fisioterapici Ospitalieri (IFO) - Xxxxxx Xxxxx National Cancer Institute - IRCCS | Department of Research and Advanced Technologies - Unit of Cellular Networks and Molecular Therapeutic Targets | Xxx Xxxx Xxxxxxxx 00 - 00000 Xxxx, Xxxxx | Head of the Department Unit "Cellular Networks and Molecular Therapeutic Targets" | 2016 | 2022 |
Other awards and honors
2017 Member of the Medical Academy of Xxxx
0000 Member of the Scientific Technical Committee of the Fondazione AIRC 2002 Il Golfo D'Oro Xxxxxxxx Xxxxxx Awards for HIPK2 identification and studies
Other CV informations
2011 - International Patent PCT/IT2011/000018
Test and related-kit for the identification of ataxia-telangiectasia heterozygous carriers 2010 - Italian Patent Brev/gc X-00000 Xxxxxx XX0000X000000
Metodo per l'identificazione in vitro di portatori sani di atassia telangiectasia e relativo kit 2005 - Italian Patent N: RM 2005 A 000144
Vettore adenovirale ricombinante di espressione di protein chinasi e usi relative
Scientific reviewer for National and International Agencies (e.g., MIUR, ISS, Wellcome Trust UK, AICR UK, Fondation contre le Cancer, BE, FIRC, Fondazione AIRC)
Scientific reviewer for National and International Journals (e.g., Cancer Res, Cell Death & Diff, Cell Rep, XXXX J, EMBO Rep, Mol Cell, Nat Cell Biol, Oncogene, PNAS)
Selected peer-reviewed publications of the PI valid for minimum expertise level | ||||||||
Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** | P.* |
HIPK2 Controls Cytokinesis and Prevents Tetraploidization by Phosphorylating Histone H2B at the Midbody | Article | 87-98 | 47 | 2012 | 10.1016/j.molcel.2012.0 4.029 | 22658722 | 30 | L |
Updates on HIPK2: A resourceful oncosuppressor for clearing cancer | Review | 63 | 31 | 2012 | 10.1186/1756-9966-31- 63 | 22889244 | 49 | L |
P53 centrosomal localization diagnoses ataxia- telangiectasia homozygotes and heterozygotes | Article | 1335- 1342 | 123 | 2013 | 10.1172/JCI67289 | 23454770 | 10 | L |
HIPK2 catalytic activity and subcellular localization are regulated by activation-loop Y354 autophosphorylation | Article | 1443- 1453 | 1833 | 2013 | 10.1016/j.bbamcr.2013.0 2.018 | 23485397 | 34 | L |
ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition | Article | 95 | 32 | 2013 | 10.1186/1756-9966-32- 95 | 24252502 | 71 | L |
Apoptosis induced by a HIPK2 full-length- specific siRNA is due to off-target effects rather than prevalence of HIPK2-Delta e8 isoform | Article | 1675- 1686 | 7 | 2016 | 10.18632/oncotarget.642 3 | 26625198 | 3 | L |
Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer | Article | 000 | 00 | 0000 | 10.1186/s13046-016- 0410-3 | 27599564 | 3 | L |
HIPK2-T566 autophosphorylation diversely contributes to UV- and doxorubicin-induced HIPK2 activation | Article | 16744- 16754 | 8 | 2017 | 10.18632/oncotarget.144 21 | 28060750 | 1 | L |
HIPK2 and extrachromosomal histone H2B are separately recruited by Aurora-B for cytokinesis | Article | 3562- 3574 | 37 | 2018 | 10.1038/s41388-018- 0191-6 | 29563611 | 2 | L |
Extrachromosomal Histone H2B Contributes to the Formation of the Abscission Site for Cell Division | Article | 1391 | 8 | 2019 | 10.3390/cells8111391 | 31694230 | 1 | L |
p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway | Article | 000 | 00 | 0000 | 10.1038/s41419-019- 2076-1 | 31699974 | 10 | L |
An Alternative Splice Variant of HIPK2 with Intron Retention Contributes to Cytokinesis | Article | 484 | 9 | 2020 | 10.3390/cells9020484 | 32093146 | 1 | L |
Variants of uncertain significance in the era of high-throughput genome sequencing: A lesson from breast and ovary cancers | Review | 46 | 39 | 2020 | 10.1186/s13046-020- 01554-6 | 32127026 | 34 | L |
HIPK2 Is Required for Midbody Remnant Removal Through Autophagy-Mediated Degradation | Article | 572094 | 8 | 2020 | 10.3389/fcell.2020.5720 94 | 33043004 | 2 | C |
HIPK2 is a potential predictive marker of a favorable response for adjuvant chemotherapy in stage II colorectal cancer | Article | 899-910 | 45 | 2021 | 10.3892/or.2020.7912 | 33650652 | 0 | L |
HIPK2 Cooperates with KRAS Signaling and Associates with Colorectal Cancer Progression. | Article | 686-698 | 20 | 2022 | 10.1158/1541- 7786.MCR-21-0628 | 35082165 | 0 | C |
* Position: F=First L=Last C=Correspondent O=Other N=Not applicable
** Autocertificated
Selected peer-reviewed publications of the PI for the evaluation CV | |||||||
Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** |
Updates on HIPK2: A resourceful oncosuppressor for clearing cancer | Review | 63 | 31 | 2012 | 10.1186/1756-9966-31- 63 | 22889244 | 49 |
HIPK2 Controls Cytokinesis and Prevents Tetraploidization by Phosphorylating Histone H2B at the Midbody | Article | 87-98 | 47 | 2012 | 10.1016/j.molcel.2012.0 4.029 | 22658722 | 30 |
Pax8 has a critical role in epithelial cell survival and proliferation | Article | e729 | 4 | 2013 | 10.1038/cddis.2013.262 | 23868062 | 33 |
ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition | Article | 95 | 32 | 2013 | 10.1186/1756-9966-32- 95 | 24252502 | 71 |
HIPK2 catalytic activity and subcellular localization are regulated by activation-loop Y354 autophosphorylation | Article | 1443- 1453 | 1833 | 2013 | 10.1016/j.bbamcr.2013.0 2.018 | 23485397 | 34 |
Abscopal effect of radiation therapy: Interplay between radiation dose and p53 status | Article | 248-255 | 90 | 2014 | 10.3109/09553002.2014. 874608 | 24350918 | 34 |
Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist | Article | 2493- 2504 | 34 | 2015 | 10.1038/onc.2014.191 | 24998848 | 40 |
MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti- apoptotic activity during early DNA damage response | Article | 228-240 | 35 | 2016 | 10.1038/onc.2015.76 | 25961923 | 26 |
MRE11 inhibition highlights a replication stress- dependent vulnerability of MYCN-driven tumors | Article | 895 | 9 | 2018 | 10.1038/s41419-018- 0924-z | 30166519 | 26 |
Variants of uncertain significance in the era of high- throughput genome sequencing: A lesson from breast and ovary cancers | Review | 46 | 39 | 2020 | 10.1186/s13046-020- 01554-6 | 32127026 | 34 |
** Autocertificated
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Fondazione AIRC | Regina Xxxxx National Cancer | 2011- | Special Program Molecular | Collaborator | 948.400,00 | AIRC 9979 |
Institute IRCCS | 2015 | and Clinical Oncology "5 per | ||||
mille" | ||||||
Development of effective | ||||||
cancer therapies based on | ||||||
functional proteomics and | ||||||
cancer stem cell targeting | ||||||
Fondazione AIRC | Regina Elena National Cancer | 2008- | Homeodomain-Interacting | Coordinator | 330.000,00 | AIRC-IG 4644 |
Institute IRCCS | 2010 | Protein Kinase2: upstream | ||||
regulators and downstream | ||||||
partners of a potent p53 | ||||||
activator | ||||||
Fondazione AIRC | Regina Elena National Cancer | 2011- | ATM heterozygosity as a | Coordinator | 360.000,00 | AIRC-IG 10568 |
Institute IRCCS | 2013 | tumor susceptibility factor in | ||||
the general population: from | ||||||
screening to therapy | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Fondazione Telethon | Regina Elena National Cancer | 2011- | MeCP2 phosphorylation and | Collaborator | 398.750,00 | GGP10032 |
Institute IRCCS | 2013 | related kinases in Rett | ||||
Syndrome and early | ||||||
infantile epileptic | ||||||
encephalopathy 2 | ||||||
Ministero della Salute | Regina Xxxxx National Cancer | 2011- | MeCP2 phosphorylation and | Coordinator | 230.769,00 | RF-IRE-2008 - |
Institute IRCCS | 2013 | related kinases in Rett | 1231829 | |||
Syndrome | xxxxx://xxxxxxx.xxxx.xx/ | |||||
Fondazione AIRC | Regina Xxxxx National Cancer | 2014- | DDR factors maintain ploidy | Coordinator | 420.000,00 | AIRC-IG 14592 |
Institute IRCCS | 2017 | by organelle-specific | ||||
functions: roles of p53 at the | ||||||
centrosome and HIPK2/H2B | ||||||
at the midbody | ||||||
Associazione Italiana | Regina Elena National Cancer | 2017- | Dissecting the contribution | Coordinator | 432.000,00 | AIRC-IG 18517 |
pre la Ricerca sul | Institute IRCCS | 2020 | of p53-mitotic centrosomal | |||
Cancro (AIRC) | localization in centrosome- | |||||
loss sensor and spindle pole | ||||||
integrity | ||||||
Ministero della Salute | Regina Xxxxx National Cancer | 2018- | Hipk2 as a prognostic | Coordinator | 410.000,00 | PE-2016-02361181 |
Institute IRCCS | 2022 | biomarker in stage I and | xxxxx://xxxxxxx.xxxx.xx/ | |||
stage II colorectal cancer: | ||||||
validation and underlying | ||||||
mechanisms | ||||||
Lega Italiana per la | Regina Elena National Cancer | 2022- | HIPK2 as a prognostic | Coordinator | 70.000,00 | LILT-2021U0001643 |
Lotta ai Tumori (LILT) | Institute IRCCS | 2023 | biomarker for liver fibrosis: | - | ||
evidence and underlying | ||||||
mechanisms | ||||||
Fondazione AIRC | Regina Elena National Cancer | 2021- | p53 mitotic centrosome | Coordinator | 810.000,00 | AIRC-IG 24403 - |
Institute IRCCS | 2025 | localization as a functional | ||||
test to predict pathogenicity | ||||||
of ATM VUS |
2.3 CO-PI Profile
Last Name: Piaggio
First Name: Xxxxxx
Last name at birth: Piaggio
Gender: F
Title: CoPI
Nationality: Italiana
Date of birth: 09/05/1962
Official H index (Scopus or Web of Science): 36.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Roma
Scopus Author Id:7005979372 ORCID ID:0000-0003-2114-1892 RESEARCH ID:J-7214-2018
Contact address
Current organisation name: Istituti fisioterapici ospitalieri - Istituto Regina Elena
Current Department / Faculty / Institute / Laboratory name: Research and Advanced Technologies/Unit of Cellular
Networks and Molecular Therapeutic Targets
Street: Xxx Xxxx Xxxxxxxx 00
Postcode / Cedex: 00144 Town: Roma
Phone:x000000000000 Phone 2:
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Sapienza University, Rome, Italy | Master's Degree / Laurea Magistrale | School of Biological Science Doctor in Biological Science - Enzymatic polymorfisms in the Dolicopoda Geniculata | 1980 | 1985 |
Sapienza University, Rome, Italy | Specialization / Specializzazione | Cyclin B1 transcription during mitosis | 1996 | 2001 |
Personal Statement:
Dr. Piaggio is an expert of transgenic animal models. Her research focuses on gene expression transcriptional
regulation in cancer cell proliferation, identifying in the past new mutant p53 protein gain of functions regulating proliferation of cancer cells. She has collaborated in the past with the PI in the seminal studies on HIPK2 discovery and functions. She will be in charge for all animal experiments.
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
IRCCS Regina Elena National Cancer Institute | Molecular Oncogenesis Laboratory | Rome, Italy | Internship | 1986 | 1986 |
European Molecular Biology Laboratory - EMBL | International Practical Course - Micro-injection and Electrotransfection of cells | Heidelberg, Germany | Participant | 1987 | 1987 |
IRCCS Regina Elena National Cancer Institute | Molecular Oncogenesis Laboratory | Rome. Italy | AIRC fellow | 1986 | 1988 |
European Molecular Biology Laboratory - EMBL | Department of Gene Expression (Chief Dr. Xxxxxxxx Xxxxxxx) | Heidelberg, Germany | Post-doctoral Fellow | 1988 | 1990 |
Research Institute for Molecular Biology - IRBM (Director Xxxxxxxx Xxxxxxx) | Molecular Biology Laboratory | Pomezia, Roma, Italy | Staff Scientist | 1990 | 1990 |
National Institute of Health - NIH | National Institute of Child Health and Human Development (NICHHD) - Laboratory of Molecular Growth Regulation | Bethesda, Mariland, USA | FIRC fellow | 1996 | 1996 |
National Institute of Health - NIH | National Institute of Child Health and Human Development (NICHHD) - Laboratory of Molecular Growth Regulation | Bethesda, Mariland, USA | Contractor | 1999 | 1999 |
National Institute of Health - NIH | National Institute of Child Health and Human Development (NICHHD) - Laboratory of Molecular Growth Regulation | Bethesda, Mariland, USA | Visiting scientist | 2003 | 2003 |
IRCCS Regina Elena National Cancer Institute | Department of Research, Diagnosis and Innovative Technologies, RIDAIT | Rome, Italy | Group leader | 1991 | 2022 |
Other awards and honors
1986 AIRC fellow
1996 FIRC fellow
2003 UICC fellow
2014 Pezcoller Begnudelli Aw.
2014-23 Full Prof. Abilitation Mol Biol BIO05/E2, Cell Biol BIO05/F1 2010-2012 SIBBM board member
2013-2018 ABCD board member 2019-2021 SPERA vicepresident
2014 Karolinska,STH, SE Opponent to PhD dissert. 2014 Expert at PhD course ESMM IEO IFOM
2015 medical Center Radiol Div. Groningen, NL. PhD dissert. Co-proponent
2010- 2015 Transgenic animal for screening of compounds that modulate cell proliferation.
Other CV informations
2012-today: editorial board member of International Journal of Genomic, Peer J., IJMS, Carcinogenesis
2014 Reviewer for XXXX-XXXXX (VQR 2004-2014).
2016 Reviewer for Fondation contre le Cancer (Belgio)
2017 Member of the Ministry Committee - FARE projects, sector ERC LS 2019, 2021 Reviewer for MIUR- PRIN 2017, 2021
2019-2020 Reviewer for Regione Piemonte - Bando PRISM-E
2019-2020 Reviewer for Central Finance and Contracting Agency (Lettonia) 2020 Reviewer for National Science Centre, Poland.
2020 Expert for Xxxxx Xxxxxxxx Xxxxx Action-Individual Felloship (H2020-MSCA-IF)
Reviewer for peer reviewed scientific journals: BMC bone, FEBS, J. Exp Clinical Cancer Res., NAR, Oncogene, PloS ONE, Experimental Hematology, Nature Communications, Cancer Research, CDDis and Disease, CDD., BBAGRM, JTM.
Selected peer-reviewed publications of the Co-PI valid for minimum expertise level | ||||||||
Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** | P.* |
Molecular imaging of nuclear factor-Y transcriptional activity maps proliferation sites in live animals | Article | 1467- 1474 | 23 | 2012 | 10.1091/mbc.E12-01- 0039 | 22379106 | 10 | L |
In vivo imaging of cell proliferation for a dynamic, whole body, analysis of undesired drug effects | Article | 296-306 | 145 | 2015 | 10.1093/toxsci/kfv056 | 25766884 | 1 | C |
A bioluminescent mouse model of proliferation to highlight early stages of pancreatic cancer: A suitable tool for preclinical studies | Article | 2-8 | 207 | 2016 | 10.1016/j.aanat.2015.11. 010 | 26704357 | 7 | L |
Dysregulation of microRNA biogenesis in cancer: The impact of mutant p53 on Drosha complex activity | Review | 45 | 35 | 2016 | 10.1186/s13046-016- 0319-x | 26971015 | 66 | L |
Infinity: An in-silico tool for genome-wide prediction of specific DNA matrices in xxXXX genomic loci | Article | e0153658 | 11 | 2016 | 10.1371/journal.pone.01 53658 | 27082112 | 5 | C |
A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas | Article | 000 | 00 | 0000 | 10.1186/s13046-016- 0393-0 | 27476114 | 54 | C |
The laminA/NF-Y protein complex reveals an unknown transcriptional mechanism on cell proliferation | Article | 2628- 2646 | 8 | 2017 | 10.18632/oncotarget.129 14 | 27793050 | 2 | L |
NF-Y in cancer: Impact on cell transformation of a gene essential for proliferation | Review | 604-616 | 1860 | 2017 | 10.1016/j.bbagrm.2016.1 2.005 | 27939755 | 35 | L |
Transgenic Animal Models to Visualize Cancer- Related Cellular Processes by Bioluminescence Imaging | Review | 000 | 00 | 0000 | 10.3389/fphar.2019.002 35 | 30930779 | 7 | L |
The clinical and prognostic value of miR-9 gene expression in Tunisian patients with bladder cancer | Article | 4743- 4750 | 46 | 2019 | 10.1007/s11033-019- 04920-6 | 31214962 | 1 | C |
miR-143 expression profiles in urinary bladder cancer: correlation with clinical and epidemiological parameters | Article | 1283- 1292 | 47 | 2020 | 10.1007/s11033-019- 05228-1 | 31863330 | 4 | C |
MITO-Luc/GFP zebrafish model to assess spatial and temporal evolution of cell proliferation in vivo | Article | 000 | 00 | 0000 | 10.1038/s41598-020- 79530-5 | 33436662 | 0 | L |
Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** | P.* |
Neutrophil extracellular traps in cancer: not only catching microbes | Review | 000 | 00 | 0000 | 10.1186/s13046-021- 02036-z | 34261496 | 4 | L |
* Position: F=First L=Last C=Correspondent O=Other N=Not applicable
** Autocertificated
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Fondazione Telethon | IRCCS-National Cancer Institute | 1999- | Biological Role of CCAAT- | Coordinator | 51.646,00 | |
Regina Xxxxx | 2000 | binding NF-Y complex in the | ||||
switch from proliferation to | ||||||
differentiation of primary | ||||||
skeletal muscle cells | ||||||
FIRB Progetti | IRCCS-National Cancer Institute | 2002- | Nuovi approcci integrati per | Collaborator | 145.000,00 | |
Negoziali 2001 | Regina Xxxxx | 2004 | l'identificazione di geni | xxxx.xx/XxxxXxxxx/000 | ||
bersaglio in genomi | 8.pdf | |||||
eucarioti | ||||||
Coordinatore: Xxxxxxx | ||||||
Xxxxxxx | ||||||
Collaboratore: Xxxxxx | ||||||
Xxxxxxx | ||||||
Convenzione CODICE | ||||||
NUMERO | ||||||
RBNE01N2ZE_002 | ||||||
AIRC | IRCCS-National Cancer Institute | 2002- | AIRC 2001: Biological role | Coordinator | 90.000,00 | |
Xxxxxx Xxxxx | 2004 | of the transcription factor | ||||
NF-Y in cell growth and | ||||||
Transformation 36 Principal | ||||||
Investigator | ||||||
Ministero della salute | IRCCS-National Cancer Institute | 2001- | Analisi del danno da Beta | Collaborator | 60.000,00 | |
Regina Xxxxx | 2003 | Amiloide e sperimentazione | x.xx/xxxxxxx/xxxxxxxXx | |||
di nuovi interventi | nitaria/dettaglioConte | |||||
terapeutici in vitro e in vivo | nutiRicercaSanitaria.j | |||||
Coordinatore Xxxxxxxx | sp?lingua=italiano&id | |||||
Capogrossi | =764&area=Ricerca | |||||
Collaboratore Xxxxxx | %20sanitaria&menu | |||||
Piaggio. | =finalizzata | |||||
Convenzione numero: ICS. | ||||||
120.4/RA00-90 | ||||||
Ministero della Salute | IRCCS-National Cancer Institute | 2003- | Caratterizzazione funzionale | Collaborator | 60.000,00 | |
Regina Xxxxx | 2005 | e molecolare degli effetti di | x.xx/xxxxxxx/xxxxxxxXx | |||
farmaci interferenti con la | nitaria/dettaglioConte | |||||
trasduzione del segnale e | nutiRicercaSanitaria.j | |||||
con la trascrizione in diverse | sp?lingua=italiano&id | |||||
neoplasie umane. | =764&area=Ricerca | |||||
Coordinator Xxxxxxx Xxxxxxx. | %20sanitaria&menu | |||||
Collaborator Xxxxxx Xxxxxxx. | =finalizzata | |||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
AIRC | IRCCS-National Cancer Institute | 2006- | Dissecting NF-Y activity and | Coordinator | 195.000,00 | |
Regina Xxxxx | 2008 | its role in cell cycle control | xx.xx/Xxxxxxxxxxx/Xxx | |||
and apoptosis. | ault.aspx; | |||||
AIRC | IRCCS-National Cancer Institute | 2009- | The NF-Y/mutp53- | Coordinator | 195.000,00 | |
Regina Xxxxx | 2011 | microRNAs Axis in Cancer | xx.xx/Xxxxxxxxxxx/Xxx | |||
Progression and | xxxx.aspx; | |||||
Chemiotheraphy Resistance | ||||||
Fondazione Cariplo | IRCCS-National Cancer Institute | 2010- | Imaging of molecular events | Collaborator | 135.000,00 | |
Xxxxxx Xxxxx | 2012 | during mammary | .it/ecm/home/ricerca/ | |||
tumorigenesis as a novel | progetti-finanziati | |||||
approach for the | ||||||
identification of new | ||||||
clinically useful tumour | ||||||
biomarkers. | ||||||
Coordinator Xxxxx Xxxxx | ||||||
Collaborator Xxxxxx Xxxxxxx | ||||||
AIRC | IRCCS-National Cancer Institute | 2012- | The transcription factor NF- | Coordinator | 260.000,00 | |
Regina Xxxxx | 2014 | Y: deciphering new | xx.xx/Xxxxxxxxxxx/Xxx | |||
molecular pathways of a | xxxx.aspx; | |||||
gene essential for | ||||||
proliferation | ||||||
Ricerca Corrente | IRCCS-National Cancer Institute | 2021- | Searching for metastasis | Coordinator | 90.000,00 | |
Regina Xxxxx | 2023 | specific druggable | ti/delibere%202021/d | |||
pathways: role of NF- | eliberazione1177del | |||||
Y/mutp53 complex in liver | 22.11.2021.pdf | |||||
metastasis from colon | ||||||
cancer |
2.3 Research Collaborators n. 2
Last Name: GRAZI
First Name: XXXX XXXX
Last name at birth:
Gender: M
Title: Additional collaborator UO1
Nationality: Italiana
Date of birth: 12/08/1961
Official H index (Scopus or Web of Science): 77.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Bologna
Scopus Author Id:13102992200 ORCID ID:0000-0002-3279-0313 RESEARCH ID:J-7215-2018
Contact address
Current organisation name: Istituti fisioterapici ospitalieri - Istituto Regina Elena
Current Department / Faculty / Institute / Laboratory name: Research and Advanced Technologies/Unit of Cellular
Networks and Molecular Therapeutic Targets
Street: Xxx Xxxx XXxxxxxx, 00
Postcode / Cedex: 00144 Town: Roma
Phone:3358015430 Phone 2: 0000000000
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Bologna University, Italy | Single-cycle master's degree / Laurea magistrale a ciclo unico | Medicine and surgery | 1980 | 1986 |
Modena University, Italy | PhD | Tumor biomarkers in the gastrointestinal tract | 1989 | 1992 |
Bologna University, Italy | Specialization / Specializzazione | Xxxxxxx xxxxxxx | 0000 | 0000 |
Xxxxxxx Xxxxxxxxxx, Xxxxxxx | Specialization / Specializzazione | First international course in split liver transplantation | 2000 | 2000 |
Essen University, Germany | Specialization / Specializzazione | Course in living donor and split liver transplantation | 2002 | 2002 |
Personal Statement:
Prof. Xxxxx is the UOC Director of general surgery in hepato-pancreatico-biliary tract. He is a brilliant surgeon specialized in hepatic surgery and liver trasplants. He is author of outstanding clinical and research publications in high impact factor journals. Within the project framework, he will be in charge of selecting the patients undergoing hepatic surgery to obtain biological samples for the generation of organotipic slice cultures.
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
Nebraska University | Unit of organ transplant | Omaha (Nebraska), USA | Visiting faculty | 1988 | 1989 |
Bologna University | Institute of clinical surgery and cardiosurgery | Bologna, Italy | Technical collaborator | 1991 | 1993 |
Policlinico Sant'Orsola- Malpighi general hospital | Policlinico Sant'Orsola- Malpighi | Bologna, Italy | Physician | 1996 | 1999 |
Policlinico Sant'Orsola- Malpighi general hospital | "Liver transplant program revision" project | Bologna, Italy | Project supervisor | 1999 | 2010 |
Policlinico Sant'Orsola- Malpighi general hospital | Unit of general surgery | Bologna, Italy | Surgeon | 1999 | 2003 |
Policlinico Sant'Orsola- Malpighi general hospital | Unit of general surgery | Bologna, Italy | Researcher | 2001 | 2004 |
Policlinico Sant'Orsola- Malpighi general hospital | Unit of liver and multi-organ transplant surgery | Bologna, Italy | Surgeon | 2003 | 2010 |
Bologna University | Medicine and surgery school | Bologna, Italy | Associate professor | 2009 | 2021 |
IRCCS Regina Elena National Cancer Institute | UOC of general surgery in hepato-pancreatico-biliary tract | Rome, Italy | UOC Director | 2010 | 2022 |
Ferrara University | Medicine and surgery school | Ferrara, Italy | Full professor | 2022 | 2022 |
Other awards and honors
Coordinator of several experimental research programs Scientific director of "Grandangolo courses in general surgery" Scientific organizer and supervisor of several surgery courses PI and co-PI of several national and international clinical trials
Co-author of several scientific publications from The Cancer Genome Atlas (TCGA)
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Fondazione del Monte | Policlinico Sant'Orsola-Malpighi | 2007 | Immunosoppressione senza | Coordinator | 61.000,00 | ChT-06-02-Cod. |
di Bologna e Ravenna | inibitori della calcineurina e | EudraCT 2007- | ||||
con utilizzo di everolimus | 006221-27 | |||||
nel trapianto di fegato per | www.fondazionedel | |||||
epatite C | xxxxx.xx | |||||
2.4 Research Collaborators n. 3
Last Name: Merla
First Name: Xxxxxxxx
Last name at birth:
Gender: M
Title: Head of UO2
Nationality: Italiana
Date of birth: 10/05/1970
Official H index (Scopus or Web of Science): 39.0
Country of residence: ITALY
Country of Birth: ITALY
Place of Birth: San Xxxxxxxx xxxxxxx
Scopus Author Id:6602627202 ORCID ID:0000-0001-5078-928X RESEARCH ID:K-4627-2012
Contact address
Current organisation name: University of Xxxxxx Xxxxxxxx XX
Current Department / Faculty / Institute / Laboratory name: Molecular Medicine and Medical Biotechnology/Genomic
Facility
Street: xxxxx Xxxxxxx 0
Postcode / Cedex: 80131 Town: Napoli
Phone:x000000000000 Phone 2:
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Trieste University, Italy | PhD | Molecular Genetics | 2011 | 2014 |
Sapienza University, Rome, Italy | Specialization / Specializzazione | Medical Genetics | 2005 | 2009 |
Bari University, Italy | Single-cycle master's degree / Laurea magistrale a ciclo unico | Genetics | 1991 | 1996 |
Personal Statement:
Xxxxx'x group is devoted to biomedical research in the field of human genetic rare diseases and cancer, ranging from clinical to basic research and therapy. Since its establishment in 2004, he has combined molecular and cell biology with omics technologies. Specifically, he has developed skills and expertise in the implementation of omics techniques such as transcriptomics - bulk RNAseq and scRNAseq - ChiPSeq, and proteomics for medical genetics and oncology research projects. More recently, he sets up and applied a genome wide DNA methylation workflow as tool for diagnostics and research on Chromatinopathies field.
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
University of Xxxxxx Xxxxxxxx XX | Department of Molecular Medicine and Medical Biotechnology | Naples, Italy | Head of the Department Genomic Facility | 2021 | 2022 |
University of Xxxxxx Xxxxxxxx XX | Department of Molecular Medicine and Medical Biotechnology | Naples, Italy | Full Professor of Molecular Biology | 2021 | 2022 |
IRCCS Casa Sollievo della Sofferenza | Laboratory of Functional and Regulatory Genomics | Xxx Xxxxxxxx Xxxxxxx (XX), Xxxxx | Unit Head | 2021 | 2022 |
IRCCS Casa Sollievo della Sofferenza | Division of Medical Genetics | San Xxxxxxxx Xxxxxxx (FG), Italy | Research Head | 2004 | 2020 |
University of Geneva Medical School | Division of Medical Genetics | Geneva, Switzerland | Research Assistant | 2001 | 2004 |
TIGEM, Telethon Institute of Genetics and Medicine | TIGEM | Milan and Naples, Italy | AIRC Research Fellow | 1998 | 2001 |
IRCCS Casa Sollievo della Sofferenza Hospital | Molecular Oncology | San Xxxxxxxx Xxxxxxx (FG), Italy | Research Fellow | 1996 | 1998 |
Other awards and honors
1998-2001 FIRC (Federazione Italiana Ricerca Cancro) Long Term Fellow (three years) 2019 Ambassador for KABUKI Award, AMBASSADOR DAY 2019
2019 Commendation for research activities, IRCCS Casa Sollievo della Sofferenza, San Xxxxxxxx Xxxxxxx, Italy
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Horizon Europe Framework Programme (HORIZON) | Università degli Studi di Xxxxxx Xxxxxxxx XX | 2022- 2024 | CHROM_RARE - Unveiling the molecular basis of chromatinopathies to delineate innovative therapeutic solutions | Collaborator | 260.000,00 | xxxxx://xx.xxxxxx.xx/x esearch/participants/ portal/desktop/sedia/ opportunities/fp7/ind ex.html |
XXXXXX XXXXXXX Foundation | IRCCS Casa Sollievo della Sofferenza | 2022 | Dissecting Interplay between 3-D chromatin architecture and transcriptional profiles in Type 1 Kabuki syndrome | Coordinator | 40.000,00 | xxxxx://xxx.xxxxxxxx .xxxxxxxxxxxxxxxx.xxx /call-for- projets/funded- projects-2021/ |
H2020 MSCA Innovative Training Network | IRCCS Casa Sollievo della Sofferenza | 2018- 2022 | TRIM NET - Training network in drug discovery targeting TRIM Ubiquitin ligases indisease | Collaborator | 261.500,00 | xxxxx://xx.xxxxxx.xx/x nfo/funding- tenders/opportunities /portal/screen/opport unities/ |
XXXXXX XXXXXXX Foundation | IRCCS Casa Sollievo della Sofferenza | 2016 | Cellular modeling to functionally dissect Kabuki Syndrome, implications for diagnosis, therapeutic and clinical care | Coordinator | 26.000,00 | xxxxx://xxx.xxxxxxxx .xxxxxxxxxxxxxxxx.xxx /call-for-projets/call- for-projects-2016/ |
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
TELETHON Foundation | IRCCS Casa Sollievo della Sofferenza | 2015 | Transcriptional and epigenetic dysfunction in Xxxxxxxx Xxxxxx and 7q11.23 microduplication syndromes | Collaborator | 100.000,00 | xxxxx://xxx.xxxxxxxx.x t/cosa- facciamo/ricerca/pro getti- finanziati/?gclid=Cjw KCAjwve2TBhByEiw AaktM1I8diQljCH0_B xZ_eZrEhyeVJCRoE gvkJU9tvbfMXvy- nvW8RDT5RBoCi8U QAvD_BwE |
AIRC | IRCCS Casa Sollievo della Sofferenza | 2014 | Dissecting TRIM8 Functions in the pathogenesis of Glioblastoma | Coordinator | 380.000,00 | xxxxx://xxx.xxxxxxxxx xxxxxxxxxxx.xxxx.xx/ |
TELETHON Foundation | IRCCS Casa Sollievo della Sofferenza | 2014 | An integrated strategy to functionally dissect the genetic and epigenetic mechanisms underlying Kabuki Syndrome | Coordinator | 415.000,00 | xxxxx://xxx.xxxxxxxx.x t/cosa- facciamo/ricerca/pro getti- finanziati/?gclid=Cjw KCAjwve2TBhByEiw AaktM1I8diQljCH0_B xZ_eZrEhyeVJCRoE gvkJU9tvbfMXvy- nvW8RDT5RBoCi8U QAvD_BwE |
Ministry of Foreign Affairs - Programmi Esecutivi ITA-ARG | IRCCS Casa Sollievo della Sofferenza | 2009- 2010 | Protocolli Diagnostici, Analisi Molecolari e Funzionali nello Studio della Sindrome di Xxxxxxxx | Coordinator | 216.000,00 | /diplomazia- culturale-e- diplomazia- scientifica/coopersci entificatecnologica/pr ogrammiesecutivi/ |
XXXXXX XXXXXXX Foundation | IRCCS Casa Sollievo della Sofferenza | 2007 | The analysis of Ubiquitin- mediated Proteolysis as pathological mechanism in the Xxxxxxxx Xxxxxx Syndrome | Coordinator | 30.000,00 | xxxxx://xxx.xxxxxxxx .xxxxxxxxxxxxxxxx.xxx / |
TELETHON Foundation | IRCCS Casa Sollievo della Sofferenza | 2006 | Genotype-phenotype correlations in Xxxxxxxx- Xxxxxx Syndrome individuals through the analysis of global gene expression changes by microarray tools | Coordinator | 115.000,00 | xxxxx://xxx.xxxxxxxx.x t/cosa- facciamo/ricerca/pro getti- finanziati/?gclid=Cjw KCAjwve2TBhByEiw AaktM1I8diQljCH0_B xZ_eZrEhyeVJCRoE gvkJU9tvbfMXvy- nvW8RDT5RBoCi8U QAvD_BwE |
2.5 Research Collaborators n. 4
Last Name: xxxxx
First Name: xxxxxxxxx
Last name at birth:
Gender: M
Title: Head of UO3
Nationality: italiana
Date of birth: 29/08/1964
Official H index (Scopus or Web of Science): 33.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: palermo
Scopus Author Id:7004583138 ORCID ID:0000-0002-3590-382X RESEARCH ID:AHI-1094-2022
Contact address
Current organisation name: Istituto Nazionale Tumori IRCCS Fondazione X. Xxxxxxx
Current Department / Faculty / Institute / Laboratory name: Division of Abdominal Oncology
Street: Via Xxxxxxx Xxxxxxx
Postcode / Cedex: 80131 Town: napoli
Phone:x000000000000 Phone 2:
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Naples University, Italy | Single-cycle master's degree / Laurea magistrale a ciclo unico | Medicine and Surgery | 1984 | 1990 |
Naples University, Italy | Specialization / Specializzazione | Infectious Disease | 1990 | 1994 |
Udine University, Italy | Specialization / Specializzazione | Medical Oncology | 1998 | 2002 |
Personal Statement:
Dr Xxxxx is an expert in metastatic disease of abdominal cancers. In this field he has made a substantial contribution to radiomics, molecular characterization, and innovative therapeutic strategies for rare malignant tumors of the digestive tract. Within the project framework, he will be responsible for patient selection, liver samples and clinical data
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
General Hospital of San Xxxxxxxxx, California | AIDS Division Oncology Division | San Xxxxxxxxx (CA), USA Palo Alto (CA), USA | Visiting fellow | 1995 | 1995 |
Centro di Riferimento Oncologico di Aviano | Division of Medical Oncology A | Aviano, Italy | Dirigente Medico | 1995 | 2003 |
Istituto Nazionale Tumori IRCCS Fondazione X. Xxxxxxx | Division of Medical Oncology B | Naples, Italy | Dirigente Medico | 2003 | 2022 |
Istituto Nazionale Tumori IRCCS Fondazione X. Xxxxxxx | Unit of Innovative therapies for abdominal metastases - Dept. of Abdominal Oncology | Naples, Italy | Head of Unit | 2018 | 2022 |
Other awards and honors
none
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
n/a | n/a | n/a | n/a | Collaborator | 0,00 | n/a |
2.6 Research Collaborators n. 5
Last Name: XXXXXXX
First Name: XXXXXXX
Last name at birth: Xxxxxxx
Gender: M
Title: Head of UO4
Nationality: Italiana
Date of birth: 01/03/1968
Official H index (Scopus or Web of Science): 54.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Napoli
Scopus Author Id:7006373556 ORCID ID:0000-0002-3826-5237 RESEARCH ID:ABH-8606-2020
Contact address
Current organisation name: Verona University Hospital Trust (AOUI Verona)
Current Department / Faculty / Institute / Laboratory name: Department of Medicine/Section of Oncology
Street: X.xx XX Xxxxx 00
Postcode / Cedex: 37134 Town: Verona
Phone:00393391446626 Phone 2: 0000000000
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Sapienza University, Rome, Italy | Single-cycle master's degree / Laurea magistrale a ciclo unico | Medicine and Surgery | 1986 | 1992 |
Sapienza University, Rome, Italy | Specialization / Specializzazione | Medical Oncology | 1992 | 1996 |
USMLE, USA | Specialization / Specializzazione | ECFMG certification in General Medicine | 1998 | 1998 |
University of Texas, M.D. Xxxxxxxx Cancer Center, Houston, TX, USA | Specialization / Specializzazione | Post-doctoral fellow in signal transduction inhibition as a therapeutic strategy in oncology | 1999 | 2002 |
Personal Statement:
Xxxx Xxxxxxx is an expert in discovery, development and clinical experimentation of new anticancer and molecularly targeted drugs, from the laboratory to the clinic. In this field he has made a substantial contribution to the discovery and development of several molecularly targeted drugs, some of which have entered clinical practice in oncology and to the identification and analysis of molecular biomarkers as predictors of response to therapy. Within the project framework, he will be responsible for clinical and model data analyses
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
Xxxxxx Xxxxx National Cancer Institute IRCCS | Division of Medical Oncology 1 | Rome, Italy | Senior staff member, attending physician | 2002 | 2018 |
Regina Elena National Cancer Institute IRCCS | Centro Studi Early Phase (CSEP) | Rome, Italy | Medical Director | 2018 | 2018 |
University of Verona - School of Medicine | Section of Oncology, Dept. of Medicine | Verona, Italy | Full professor and Section Head | 2018 | 2022 |
Verona University and Hospital Trust (AOUI Verona) | Division of Oncology | Verona | Director | 2018 | 2022 |
University of Verona - School of Medicine | Specialty School in Medical Oncology | Verona | Director | 2018 | 2022 |
Verona University and Hospital Trust (AOUI Verona) | COVID19 logistics for the Policlinico G.B. Rossi | Verona | Special Commissioner | 2020 | 2022 |
Centro Ricerche Cliniche di Verona Srl (CRC) | Board of Administrators | Verona | Member | 2018 | 2022 |
Other awards and honors
1992 - Winner AIRC fellowship for Oncological Research 1994 - Degree's Thesis Award, Cenci Bolognetti Foundation
1999-2000 - American Cancer Society International Fellowship for Beginning Investigators by UICC 1999 - Award of the National Committee for Biomedical Sciences (CNR)
1992 - member of Italian Association for Medical Oncology for Guidelines on Diagnosis and Treatment of Pancreatic Cancer
2016 Elected Member of the Board of Directors, Italian Association for the Study of Pancreas
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Fondazione AIRC | Regina Xxxxx National Cancer | 2016- | Beyond tumor cell targeting | Coordinator | 374.000,00 | |
Institute IRCCS | 2018 | with pathway inhibitors in | xx.xx/Xxxxxxxxxxx/Xxx | |||
human melanoma: role of | jectSummary.aspx?p | |||||
the microenvironment | rojectid=14762 | |||||
Ministero della Salute | University of Verona | 2019- | Applicative translation of the | Collaborator | 75.000,00 | xxxxx://xxxxxxxxxxx.x |
2021 | results of genomic research | rg/cosa-facciamo/ | ||||
on pancreatic cancer | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
MIUR - PRIN | University of Verona | 2022- | Gene/environment | Coordinator | 819.129,00 | xxxxx://xxxx.xxx.xxx.xx |
2024 | interactions in breast and | / | ||||
thyroid cancers: defining the | ||||||
biological role of and | ||||||
actioning endocrine | ||||||
disruptors (ED) and lifestyle | ||||||
to develop rational | ||||||
therapeutic/preventive | ||||||
interventions. ASTEROID- | ||||||
breASt Thyroid cancERs | ||||||
endOcrIne Disruptors |
2.7 Research Collaborators n. 6 - Under 40
Last Name: XXXXXXX
First Name: XXXXXX
Last name at birth:
Gender: M
Title: Additional collaborator UO1
Nationality: Italiana
Date of birth: 08/05/1984
Official H index (Scopus or Web of Science): 6.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Roma
Scopus Author Id:56650772700 ORCID ID:0000-0001-6397-3641 RESEARCH ID:ABA-2484-2021
Contact address
Current organisation name: Istituti fisioterapici ospitalieri - Istituto Regina Elena
Current Department / Faculty / Institute / Laboratory name: Research and Advanced Technologies/Unit of Cellular
Networks and Molecular Therapeutic Targets
Street: XXX XXXX XXXXXXXX, 00
Postcode / Cedex: 00144 Town: Roma
Phone:x000000000000 Phone 2: 0000000000
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Tuscia University, Viterbo, Italy | PhD | Molecular Biology and Genetics | 2012 | 2015 |
Tor Vergata University, Rome, Italy | Master's Degree / Laurea Magistrale | Biotechnology | 2008 | 2010 |
Tor Vergata University, Rome, Italy | Bachelor Degree / Laurea Triennale | Biotechnology | 2005 | 2008 |
Personal Statement:
Dr Xxxxxxx has a strong expertise about Hipk2 kinase in pathological pathways. In particular, he has discovered a role of HIPK2 deficiency in the induction of CIN and tumorigenesis. He will be responsible for the experiments with HIPK2 inhibitors and with Hipk2 knocked-out animals.
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
IRCCS Regina Elena National Cancer Institute | Cellular networks and molecular therapeutic targets | Rome, Italy | Senior Researcher | 2020 | 2022 |
Consiglio Nazionale delle Ricerche | Institute of biology and cell pathology | Rome, Italy | Researcher/Post-doc | 2019 | 2020 |
IRCCS Regina Elena National Cancer Institute | Cellular networks and molecular therapeutic targets | Rome, Italy | Researcher/Post-doc | 2016 | 2019 |
IRCCS Regina Elena National Cancer Institute | Molecular oncogenesis lab, Dept. of experimental oncology | Rome, Italy | Researcher/Post-doc | 2015 | 2016 |
IRCCS Regina Elena National Cancer Institute | Molecular oncogenesis lab, Dept. of experimental oncology | Rome, Italy | PhD Student | 2012 | 2015 |
IRCCS Regina Elena National Cancer Institute | Molecular oncogenesis lab, Dept. of experimental oncology | Rome, Italy | post graduate Researcher | 2011 | 2012 |
Other awards and honors
2016 Fondazione Italiana Ricerca sul Xxxxxx Xxxxx e Xxxxxxx Xxxxx Fellowship
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Lega Italiana per la | Regina Elena National Cancer | 2022- | HIPK2 as a prognostic | Collaborator | 70.000,00 | LILT-2021U0001643 |
Lotta ai Tumori (LILT) | Institute IRCCS | 2023 | biomarker for liver fibrosis: | |||
evidence and underlying | ||||||
mechanisms | ||||||
AIRC | Regina Elena National Cancer | 2021- | p53 mitotic centrosome | Collaborator | 810.000,00 | xxxxx://xxx.xxxxxxxxx |
Institute IRCCS | 2025 | localization as a functional | xxxxxxxxxxx.xxxx.xx/ | |||
test to predict pathogenicity | ||||||
of ATM VUS | ||||||
Ministero della Salute | Regina Xxxxx National Cancer | 2018- | Hipk2 as a prognostic | Collaborator | 410.000,00 | xxxxx://xxxxxxx.xxxx.xx/ |
Institute IRCCS | 2022 | biomarker in stage I and | ||||
stage II colorectal cancer: | ||||||
validation and underlying | ||||||
mechanisms | ||||||
Telethon | Consiglio Nazionale delle Ricerche | 2017 | Hereditary spastic | Collaborator | 61.750,00 | |
- Istituto Biologia e Patologia | paraplegia: investigations | t/cosa- | ||||
Molecolari | on the regulation of spastin | facciamo/ricerca/pro | ||||
protein mediated by the | getti- | |||||
kinase HIPK2 in proliferating | finanziati/paraplegia- | |||||
cells and in neurons | spastica-ereditaria- | |||||
indagine-sulla- | ||||||
regolazione-della- | ||||||
proteina-spastina-da- | ||||||
parte-della-chinasi- | ||||||
hipk2-in-cellule- | ||||||
proliferanti-e-nei- | ||||||
neuroni | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
AIRC | Consiglio Nazionale delle Ricerche | 2015- | Cytokinesis failure, | Collaborator | 180.000,00 | xxxxx://xxx.xxxxxxxxx |
- Istituto Biologia e Patologia | 2018 | chromosomal instability and | xxxxxxxxxxx.xxxx.xx/ | |||
Molecolari | tumorigenicity: HIPK2 role in | |||||
pancreatic cancer |
2.8 Research Collaborators n. 7 - Under 40
Last Name: Pallocca
First Name: Xxxxxx
Last name at birth:
Gender: M
Title: Additional collaborator UO1
Nationality: Italia
Date of birth: 10/03/1987
Official H index (Scopus or Web of Science): 17.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Velletri
Scopus Author Id:55919285100 ORCID ID:0000-0002-7756-3579 RESEARCH ID:K-9259-2016
Contact address
Current organisation name: Istituti fisioterapici ospitalieri - Istituto Regina Elena
Current Department / Faculty / Institute / Laboratory name: Research and Advanced Technologies/Unit of Cellular
Networks and Molecular Therapeutic Targets
Street: Xxx Xxxx Xxxxxxxx 00
Postcode / Cedex: 00144 Town: Roma
Phone:x000000000000 Phone 2:
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Sapienza University, Rome, Italy | Bachelor Degree / Laurea Triennale | Computer Science | 2008 | 2010 |
Sapienza University, Rome, Italy | Master's Degree / Laurea Magistrale | Computer Science | 2010 | 2013 |
Personal Statement:
Since 2014 Dr. Xxxxxxxx has been working at Regina Elena National Cancer Institute, where he is coordinating the Bioinformatics group since 2017. He leads a working group on clinical reporting for Alleanza Contro il Cancro, the Italian Research Oncology Network, and teached Bioinformatics courses for Sapienza University in 2018-2020. His main research interests are results reproducibility, biomarker discovery and validation from -omics data, especially Immuno-Informatics approaches for bulk RNA-seq data reduction.
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
Hubrecht Institute | Cuppen group | Utrecht, Netherlands | Internship | 2011 | 2012 |
Sapienza University | Bioinformatics | Rome, Italy | Research Fellow | 2012 | 2013 |
IRCCS Regina Elena National Cancer Institute | UOSD Biostatistics, Bioinformatics and Clinical Trial Center | Rome, Italy | Bioinformatician | 2014 | 2017 |
Sapienza University | Bioinformatics | Rome, Italy | Contract professor | 2018 | 2021 |
IRCCS Regina Elena National Cancer Institute | UOSD Biostatistics, Bioinformatics and Clinical Trial Center | Rome, Italy | Group Leader and Bioinformatics Coordinator | 2018 | 2025 |
Other awards and honors
June 2018 - "Xxxxxx X'Xxxxxxx Xxxxxxx" award as a best under 35 oral presentation - SIBBM 2018
October 2018 - Best oral presentation at the Italian Society for the Pancreas study (SIC-AISP 2018), special session at 2018 SIC
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
Ministry of Health - | Xxxxxx Xxxxx National Cancer | 2021- | Programma nazionale di | Coordinator | 28.368,00 | RCR2021 |
Alleanza Contro il | Institute IRCCS | 2022 | oncologia personalizzata | www.alleanzacontroil | ||
Cancro | per gli IRCCS della Rete | xxxxxx.xx/ | ||||
ACC | ||||||
Bioinformatics-Genomics | ||||||
Grant | ||||||
Horizon Europe | Regina Elena Cancer Institute | 2021- | CanServ Consortium for | Collaborator | 80.000,00 | xxxxx://xx.xxxxxx.xx/x |
Framework | IRCCS | 2022 | BBMRI-IT regarding digital | nfo/funding- | ||
Programme | analysis services across the | tenders/opportunities | ||||
(HORIZON) | Biobank Network | /portal/screen/opport | ||||
unities/topic- | ||||||
details/horizon-infra- | ||||||
2021-serv-01-01 | ||||||
2.9 Additional Research Collaborators n. 2 - Under 40 to hire
Last Name: Xxxxx
First Name: Xxxxxxxxx Xxxxx
Last name at birth:
Gender: F
Title: Under40 to hire
Nationality: Italiana
Date of birth: 21/11/1990
Official H index (Scopus or Web of Science): 10.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Foggia
Scopus Author Id:57200130754 ORCID ID:0000-0002-3032-6955 RESEARCH ID:J-2192-2018
Contact address
Current organisation name: University of Xxxxxx Xxxxxxxx XX
Current Department / Faculty / Institute / Laboratory name: Molecular Medicine and Medical Biotechnology/Genomic
Facility
Street: Xxxxx Xxxxx Xxx
Xxxxxxxx / Xxxxx: 00000 Town: San Xxxxxxxx Xxxxxxx
Phone:x000000000000 Phone 2:
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Siena University, Italy | Master's Degree / Laurea Magistrale | Sanitary Biology | 2015 | 2019 |
Foggia University, Italy | Bachelor Degree / Laurea Triennale | Biomedical Laboratory Techniques | 2009 | 2013 |
Personal Statement:
Since 2015, I joined Professor Xxxxx'x group at IRCCS Casa Sollievo della Sofferenza. Since then I have been working on both diagnostic and research on rare Mendelian disorders, mainly Chromatinopathies. I became familiar with high- throughput NGS sequencing methods and I gained skills and expertise in both technical and analysis fields. Recently, using Infinium Methylation EPIC technology, I started to investigate the DNA methylation profile of a large cohort of Chromatinopathies samples, contributing in the identification of specific episignatures; a study made in collaboration with Professor Xxxxxxxxx from London Health Sciences in Canada.
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
IRCCS Casa Sollievo della Sofferenza | Laboratory of Regolative and Functional Genomics | Xxx Xxxxxxxx Xxxxxxx (XX), Xxxxx | Laboratory Technician and Research collaborator | 2021 | 2022 |
IRCCS Casa Sollievo della Sofferenza | Division of Medical Genetics | San Xxxxxxxx Xxxxxxx (FG), Italy | Research collaborator | 2019 | 2021 |
IRCCS Casa Sollievo della Sofferenza | Division of Medical Genetics | San Xxxxxxxx Xxxxxxx (FG), Italy | Laboratory Technician | 2015 | 2019 |
Other awards and honors
n/a
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
n/a | n/a | n/a | n/a | Collaborator | 0,00 | n/a |
2.10 Additional Research Collaborators n. 3 - Under 40 to hire
Last Name: Xxxxxxxxx
First Name: Xxxxxxxx
Last name at birth: Xxxxxxxxx
Gender: F
Title: Under40 to hire
Nationality: Italiana
Date of birth: 06/12/1995
Official H index (Scopus or Web of Science): 0.0
Country of residence: ITALY Country of Birth: ITALY Place of Birth: Terlizzi
Scopus Author Id:n/a ORCID ID:0000-0003-1200-3869 RESEARCH ID:AIC-4377-2022
Contact address
Current organisation name: University of Xxxxxx Xxxxxxxx XX
Current Department / Faculty / Institute / Laboratory name: Molecular Medicine and Medical Biotechnology/Genomic
Facility
Street: Xxxxx xxxxxxxxxx
Xxxxxxxx / Xxxxx: 00000 Town: San Xxxxxxxx Xxxxxxx
Phone:x000000000000 Phone 2:
Education / training | ||||
Educational institution and location | Degree | Field of study | From year | To year |
Bari University, Italy | Master's Degree / Laurea Magistrale | Medical Biotechnology and Molecular Biology | 2015 | 2018 |
Bari University, Italy | Bachelor Degree / Laurea Triennale | Medical and Pharmaceutical Biotechnology | 2019 | 2021 |
Personal Statement:
As a young biotechnologist, Dr Xxxxxxxxx will be in charge in the UO2 for genomic and epigenetic analyses of mouse and hLSC samples.
Positions and honors
Positions | |||||
Institution | Division / Research group | Location | Position | From year | To year |
Fondazione IRCCS Casa Sollievo della Sofferenza | Laboratory of Regulatory and Functional Genomics | Xxx Xxxxxxxx Xxxxxxx (XX), Xxxxx | Biotechnologist collaborator | 2021 | 2022 |
Other awards and honors
Paparella A*, Xxxxx GM*, di Venere E, Xxxxxx E, Xxxxx T, Castellana S, Xxxxxxx J, XxXxxxxx H, Xxxxxxxxx B, Xxxxxxxxx L, Xxxxxxx MC, Xxxxx G. Genome-wide DNA methylation profiling and exome sequencing resolved a long-time misdiagnosed case, J Hum Xxxxx. 2022. IN PRESS
Poster presentation at the XXIV SIGU National Congress 17-19 November 2021 - Combined application of omics strategies for the diagnosis of NEDSDV syndrome in a long time unsolved clinical case
Grant | ||||||
Funded by Institution | Researcher inst. where xxxxx is/was performed | Year | Title | Position in Projects | Fund (euro) | Source website grant listed |
none | none | n/a | n/a | Collaborator | 0,00 | n/a |
2.17 Expertise Research Collaborators
Selected peer-reviewed publications of the Research Group / Collaborators | |||||||||
Collaborato | Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** | P.* |
Piaggio Xxxxxx | Xxxxxxx-inducible factor 1-alfa induces miR-210 in normoxic differentiating myoblasts | Article | 44761- 44771 | 287 | 2012 | 10.1074/jbc.M112.42125 5 | 23148210 | 76 | O |
XXXXXXX XXXXXXX | Xxxxxxxxx versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small- cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial | Article | 239-246 | 13 | 2012 | 10.1016/S1470- 0000(00)00000-X | 00000000 | 4159 | O |
Piaggio Xxxxxx | XxXXX let-7c promotes granulocytic differentiation in acute myeloid leukemia | Article | 3648- 3654 | 32 | 2013 | 10.1038/onc.2012.398 | 22964640 | 51 | O |
xxxxx xxxxxxxxx | Xxxxxxxxxx and predictive response factors in colorectal cancer patients: Between hope and reality | Article | 15049- 15059 | 20 | 2014 | 10.3748/wjg.v20.i41.150 49 | 25386053 | 66 | O |
Xxxxx Xxxxxxxx | Molecular Analysis, Pathogenic Mechanisms, and Readthrough Therapy on a Large Cohort of Kabuki Syndrome Patients | Article | 841-850 | 35 | 2014 | 10.1002/humu.22547 | 24633898 | 65 | L |
XXXXXXX XXXXXX | HIPK2 deficiency causes chromosomal instability by cytokinesis failure and increases tumorigenicity | Article | 10320- 10334 | 6 | 2015 | 10.18632/oncotarget.358 3 | 25868975 | 15 | F |
XXXXXXX XXXXXX | Deregulation of HMGA1 expression induces chromosome instability through regulation of spindle assembly checkpoint genes | Article | 17342- 17353 | 6 | 2015 | 10.18632/oncotarget.394 4 | 26009897 | 16 | O |
xxxxx xxxxxxxxx | Xxxxxxxxxxxxx of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial | Article | 1710- 1714 | 26 | 2015 | 10.1093/annonc/mdv176 | 25851630 | 95 | O |
XXXXXXX XXXXXXX | PTEN: Multiple functions in human malignant tumors | Review | 024 | 5 | 2015 | 10.3389/fonc.2015.0002 4 | 25763354 | 280 | F |
Collaborato | Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** | P.* |
XXXXXXX XXXXXXX | Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): Sensitivity analysis of trials in melanoma, lung and genitourinary cancers | Article | e0130142 | 10 | 2015 | 10.1371/journal.pone.01 30142 | 26086854 | 351 | O |
Piaggio Giulia | A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas | Article | 000 | 00 | 0000 | 10.1186/s13046-016- 0393-0 | 27476114 | 54 | C |
Piaggio Giulia | Dysregulation of microRNA biogenesis in cancer: The impact of mutant p53 on Drosha complex activity | Review | 45 | 35 | 2016 | 10.1186/s13046-016- 0319-x | 26971015 | 66 | L |
xxxxx xxxxxxxxx | Xxxxxxxxxxx in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti-BIL study) | Article | 574-581 | 122 | 2016 | 10.1002/cncr.29778 | 26540314 | 88 | O |
XXXXXXX XXXXXXX | Avelumab in patients with chemotherapy-refractory metastatic Xxxxxx cell carcinoma: a multicentre, single-group, open-label, phase 2 trial | Article | 1374- 1385 | 17 | 2016 | 10.1016/S1470- 2045(16)30364-3 | 27592805 | 791 | O |
Xxxxx Xxxxxxxx | Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) | Review | 1-222 | 12 | 2016 | 10.1080/15548627.2015. 1100356 | 26799652 | 3746 | O |
XXXXXXX XXXXXX | CDKL5 localizes at the centrosome and midbody and is required for faithful cell division | Article | 6228 | 7 | 2017 | 10.1038/s41598-017- 05875-z | 28740074 | 15 | O |
xxxxx xxxxxxxxx | Use of Complementary and Alternative Medicine (CAM) in cancer patients: An Italian multicenter survey | Article | 24401- 24414 | 8 | 2017 | 10.18632/oncotarget.142 24 | 28212560 | 79 | O |
XXXXX XXXX XXXX | Identification of miR-31-5p, miR-141-3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor- recipient age-mismatch in transplants | Article | 262-272 | 16 | 2017 | 10.1111/acel.00000 | 00000000 | 00 | L |
xxxxx xxxxxxxxx | Metastatic colorectal cancer: Role of target therapies and future perspectives | Review | 421-429 | 18 | 2018 | 10.2174/1568009617666 170209095143 | 28183254 | 00 | X |
Xxxxx Xxxxxxxxx Xxxxx | XXXX00 regulates Beclin 1 proautophagic activity | Article | 908-919 | 1865 | 2018 | 10.1016/j.bbamcr.2018.0 3.011 | 29604308 | 30 | O |
Collaborato | Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** | P.* |
Xxxxx Xxxxxxxxx Xxxxx | MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences | Article | 2152- 2166 | 32 | 2018 | 10.1038/s41375-018- 0033-0 | 29467491 | 55 | O |
Xxxxxxxx Xxxxxx | Xxxx non-coding MIR205HG depletes Hsa-miR-590-3p leading to unrestrained proliferation in head and neck squamous cell carcinoma | Article | 1850- 1868 | 8 | 2018 | 10.7150/thno.22167 | 29556360 | 49 | O |
XXXXX XXXX XXXX | Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer | Article | 291- 304.e6 | 173 | 2018 | 10.1016/j.cell.2018.03.0 00 | 00000000 | 000 | O |
XXXXX XXXX XXXX | An Integrated TCGA Pan- Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics | Article | 400- 416.e11 | 173 | 2018 | 10.1016/j.cell.2018.02.0 00 | 00000000 | 000 | O |
XXXXX XXXX XXXX | Oncogenic Signaling Pathways in The Cancer Genome Atlas | Article | 321- 337.e10 | 173 | 2018 | 10.1016/j.cell.2018.03.0 00 | 00000000 | 000 | O |
XXXXX XXXX XXXX | The Immune Landscape of Cancer | Article | 812- 830.e14 | 48 | 2018 | 10.1016/j.immuni.2018.0 3.023 | 29628290 | 1556 | O |
XXXXXXX XXXXXX | HIPK2 phosphorylates the microtubule-severing enzyme spastin at S268 for abscission | Article | 684 | 8 | 2019 | 10.3390/cells8070684 | 31284535 | 9 | O |
XXXXXXX XXXXXX | p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway | Article | 000 | 00 | 0000 | 10.1038/s41419-019- 2076-1 | 31699974 | 13 | O |
Xxxxxxxx Xxxxxx | Combinations of immuno- checkpoint inhibitors predictive biomarkers only marginally improve their individual accuracy | Article | 000 | 00 | 0000 | 10.1186/s12967-019- 1865-8 | 31014354 | 00 | X |
Xxxxxxxx Xxxxxx | Xxxxxxxxx as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases | Article | 000 | 00 | 0000 | 10.1038/s41419-019- 1453-0 | 30814510 | 53 | O |
Xxxxxxxx Xxxxxx | Xxxx as a prognostic/predictive biomarker in cancer: An unfulfilled promise? | Article | 000 | 00 | 0000 | 10.3390/cancers110404 35 | 30925702 | 53 | O |
Xxxxx Xxxxxxxxx Xxxxx | Customised next-generation sequencing multigene panel to screen a large cohort of individuals with chromatin- related disorder | Article | 760-768 | 57 | 2020 | 10.1136/jmedgenet- 2019-106724 | 32170002 | 1 | F |
Collaborato | Title | Type | Pag | Vol | Year | DOI | PMID | Cit.** | P.* |
Xxxxxxxx Xxxxxx | KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden | Article | 1746- 1754 | 31 | 2020 | 10.1016/j.annonc.2020.0 8.2105 | 32866624 | 58 | O |
XXXXXXX XXXXXXX | Pan-cancer analysis of whole genomes | Article | 82-93 | 578 | 2020 | 10.1038/s41586-020- 1969-6 | 32025007 | 739 | O |
Xxxxx Xxxxxxxx | ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population | Article | 1602- 1614 | 28 | 2020 | 10.1038/s41431-020- 0691-z | 32681121 | 97 | O |
Piaggio Giulia | Fifth-week immunogenicity and safety of anti-SARS-CoV- 2 BNT162b2 vaccine in patients with multiple myeloma and myeloproliferative malignancies on active treatment: preliminary data from a single institution | Article | 81 | 14 | 2021 | 10.1186/s13045-021- 01090-6 | 34001183 | 71 | O |
Xxxxx Xxxxxxxxx Xxxxx | Association of toll-like receptor 7 variants with life-threatening COVID-19 disease in males: Findings from a nested case- control study | Article | e67569 | 10 | 2021 | 10.7554/eLife.67569 | 33650967 | 41 | O |
Xxxxx Xxxxxxxxx Xxxxx | Xxxxxxx the human genetic architecture of COVID-19 | Article | 472-477 | 600 | 2021 | 10.1038/s41586-021- 03767-x | 34237774 | 84 | O |
Xxxxx Xxxxxxxx | Genetic mechanisms of critical illness in COVID-19 | Article | 92-98 | 591 | 2021 | 10.1038/s41586-020- 03065-y | 33307546 | 342 | O |
Xxxxx Xxxxxxxx | Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) | Review | 1-382 | 17 | 2021 | 10.1080/15548627.2020. 1797280 | 33634751 | 378 | O |
* Position: F=First L=Last C=Correspondent O=Other N=Not applicable
** Autocertificated
3 - Ethics
1. HUMAN EMBRYOS/FOETUSES | |
Does your research involve Human Embryonic Stem Cells (hESCs)? | No |
Does your research involve the use of human embryos? | No |
Does your research involve the use of human foetal tissues / cells? | No |
2. HUMANS | |
Does your research involve human participants? | No |
Does your research involve physical interventions on the study participants? | No |
3. HUMAN CELLS / TISSUES | |
Does your research involve human cells or tissues (other than from Human Embryos/ Foetuses? | Yes |
4. PERSONAL DATA | |
Does your research involve personal data collection and/or processing? | Yes |
Does your research involve further processing of previously collected personal data (secondary use)? | Yes |
5. ANIMALS | |
Does your research involve animals? | Yes |
6. ENVIRONMENT & HEALTH and SAFETY | |
Does your research involve the use of elements that may cause harm to the environment, to animals or plants? | No |
Does your research deal with endangered fauna and/or flora and/or protected areas? | No |
Does your research involve the use of elements that may cause harm to humans, including research staff? | No |
7. DUAL USE | |
Does your research involve dual-use items in the sense of Regulation 428/2009, or other items for which an | No |
8. EXCLUSIVE FOCUS ON CIVIL APPLICATIONS | |
Could your research raise concerns regarding the exclusive focus on civil applications? | No |
9. MISUSE | |
Does your research have the potential for misuse of research results? | No |
10. OTHER ETHICS ISSUES | |
Are there any other ethics issues that should be taken into consideration? Please specify | No |
X
I confirm that I have taken into account all ethics issues described above and that, if any ethics issues apply, I will complete the ethics self-assessment and attach the required documents.
4 - Call-specific questions
Eligibility | |
I acknowledge that I am aware of the eligibility requirements for applying as specified in the Call- PNRRXXXX_M6/C2, and certify that, to the best of my knowledge my application is in compliance with all these requirements. I understand that my proposal may be declared ineligible at any point during the evaluation or granting process if it is found not to be compliant with these eligibility criteria. | X |
I confirm that the proposal that I am about to submit draws substantially don’t repeat on an existing or recently finished GRANT funded. | X |
Data-Related Questions and Data Protection (Consent to any question below is entirely voluntary. A positive or negative answer will not affect the evaluation of your project proposal in any form and will not be communicated to the evaluators of your project.) | |
For communication purposes only, the MoH asks for your permission to publish,in whatever form and medium, your name, the proposal title, the proposal acronym, the panel, and host institution, should your proposal be retained for funding. | X |
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5 – Description Project
Summary description
Chronic liver diseases (CLDs) are an increasing global health problem. They are highly prevalent and silent, related to different causes of fibrosis, such as alcoholic liver disease and non-alcoholic steatohepatitis (XXXX). XXXX is closely related to the triple epidemic of obesity, pre-diabetes, and diabetes and its contribution to the causes of CLDs is expected to increase in the next decade. Necroinflammation and liver fibrosis are key mechanisms in CLD progression toward cirrhosis and hepatocellular carcinoma. However, the molecular determinants are still unclear and candidate biomarkers for prevention and treatment are under intense investigation.
Here, we propose to address this issue by two complementary approaches:
1) an unbiased omics-characterization of the hepatic microenvironment performed on fresh human livers treated in organotypic slice cultures
2) exploring the anti-fibrotic activity of targeting the pro-fibrotic kinase HIPK2 on liver-specific HIPK2 KO mice and hLSCs
Background / State of the art
In the past decade, several non-invasive test for liver fibrosis, such as the Enhanced Liver Fibrosis test, FibroTest, FibroMAX, and transient elastography FibroScan® have been developed to overcome liver biopsy limitations. However, their diagnostic accuracy, cost-effectiveness, and effect on patient outcomes are still debated. In addition, they do not inform on possible candidate targets. Thus, identification of new biomarkers for liver fibrosis prevention and/or treatment is a major objective of current research.
Preclinical platforms to exploit microenvironment determinants of liver fibrosis have to include stromal and immune cells. This makes 3D organoids and their xenografts only partially suitable. To overcome these limitations, Xxxxx et al. developed a model system of organotypic slice cultures (1). They used a vibratome to cut fresh human tissue into slices that are then cultured in vitro. These slices maintain many elements of the original microenvironment and architecture for approximately one week and can be treated before subsequent analyses.
Accumulating evidence supports HIPK2 as a key determinant in tissue fibrosis and a possible target for anti-fibrosis therapy (2). Three different animal models for kidney fibrosis have been employed to identify HIPK2 as a driver of this disease (3). More recently, HIPK2 was shown to modulate HSC activation by inhibiting the TGF-beta1/SMAD3 pathway (4), indicating that HIPK2 contributes also to liver fibrosis.
Description and distribution of activities of each operating unit
To date, studies on liver fibrosis present two major difficulties. Studies done on cell cultures (even 3D multicell cultures) take into account specific cell populations but do not consider the real complexity of the tissue environment, while studies comparing liver biopsies are limited by the long and non-homogenous evolution of the disease. To overcome these limitations, this project will integrate the knowledge of basic and translational scientists (UO1), clinicians (U01, UO3, and UO4), and expert in omics techniques (UO2) and bioinformatics (UO1 and UO2). They will focus on an unbiased omic- characterization of the hepatic microenvironment performed on fresh human livers treated in organotypic slice cultures (i.e., hLSCs). To this aim, liver biopsies will be initially collected at the Regina Elena Cancer Institute where basic/translational scientists and liver surgeon (Prof. Xxxxx) work together. This will allow the use of the vibratome to cut fresh human liver slices and their subsequent culture in vitro. Once treated and processed, the slides will be either analyzed by UO1 (e.g., biochemical and imaging analyses) or sent to UO2 for omics analyses (e,g., transcriptomic, single-cell-sequencing). Omics data will be processed by both UO2 and UO1. Emerging biomarkers will be validated by pilot study on retrospective liver samples by UO3 and UO4.
In addition to the above unbiased strategy, we will also explore the anti-fibrotic activity of targeting the pro-fibrotic kinase HIPK2 using GEMMs and treating hLSCs with HIPK2 inhibitors. In addition to the Background data reported above, this hypothesis-driven part of the project is based on the following considerations. Together with the CoPI, the PI has performed seminal and largely cited studies on HIPK2 (5) and has been interested for a long time in studying the HIPK2 role in apoptosis, DNA damage response, cell proliferation, and cytokinesis. More recently, Dr Xxxxxxx, a young investigator of the same PI's Unit, and the coPI have developed a HIPK2 conditional knocked-out mouse (HIPK2 cKO) in which Hipk2 expression can be specifically deleted into specific organs by expression of the CRE-recombinase under the control of tissue specific promoters (e.g., albumin-CRE for liver specific recombination). Here, we propose to employ our large body of HIPK2 tools and experience to investigate the role of HIPK2 in the pathogenesis of liver fibrosis. To this aim, UO1 has already crossed the HIPK2 cKO mice with the albumin-CRE transgenic mice to delete HIPK2 only in the liver (HIPK2 LKO) (Fig. 1). Within this project, wild-type (WT) and HIPK2 LKO mice will be treated with standard protocols for fibrosis induction and studied in collaboration with UO2 for their omics-characterization.
Last, the staff directly involved in this project has gender equality, including four women, i.e., two group leaders and two young researchers to hire. The units within the consortium also span several regions in Italy, joining Northern Italy (UO4 in Verona), center (UO1 in Rome) and Southern Italy (UO2 and UO3 in Naples).
5.4 Specific Aims and Experimental Design
Specific aim 1
Establishment of human liver slice cultures as a tool to study hepatic microenvironment determinants of liver fibrosis.
Specific aim 2
Generation of a liver-specific HIPK2 knockout mouse model to establish the contribution of HIPK2 in liver fibrosis
Specific aim 3
Pilot validation of HIPK2 and new emerging biomarkers of liver fibrosis
Experimental design aim 1
Establishment of human liver slice cultures as a tool to study hepatic microenvironment determinants of liver fibrosis. Highly synthetic and alpha-smooth muscle actin positive myofibroblasts are key effector cells responsible for excessive extracellular matrix (ECM) deposition in normal wound healing and in the context of pathological fibrosis. Current evidence points to the pleiotropic cytokine TGF-beta1 as key mediator involved in promoting excessive myofibroblast differentiation
and fibrogenesis. The persistence of myofibroblasts is regarded to be a key event in the initiation and progression of fibrosis (6). To study these and additional aspects in the hepatic microenvironment, we will take advantage from the organotypic slice culture technique originally developed and applied to study tumor microenvironment and the complex interactions between human cancers and the immune response (7). We will establish human liver slice cultures (hLSCs) by applying the protocol described by Pillarisetty's group (1) on punch biopsies (6 mm diameter) of normal livers obtained from patients undergoing abdominal surgery for primary or secondary liver cancers (e.g., liver metastases of colorectal cancer, pancreatic cancer, breast cancer) and who provided prior written informed consent under a specific research protocol approved by the Ethical Committee. We will use a Vibratome to cut fresh human liver samples into 250 micron thick slices under sterile conditions, and culture slices on cell culture inserts with 0.4 micron pore to produce our hLSCs (Fig. 3). Replicate LSCs will be cultured in the presence of TGF-beta1, to activate hepatic stellate cells (HSCs) into myofibroblasts and stimulate ECM deposition, or TGF-solvent, as control. To define the best time and culture conditions to perform the omics-characterization, hLSCs will be analyzed in the following week by time-lapse (IncuCyte) and for fibrosis induction by picrosirius red and Xxxxxx'x trichrome staining, qRT-PCR and multiple immunofluorescence (IF) for known fibrosis pathways (see Aim 2). We will also assess whether induction of the "excluded volume effect" by macromolecular crowding, which is known to dramatically enhance ECM deposition in fibroblast cultures (8), significantly improves fibrosis in hLSCs.
Once defined the best time and culture conditions, hSCLs treated or not with TGF-beta1 will be analyzed by single-cell-
sequencing (scRNA-Seq). A pilot study will be first performed to gain preliminary data of power analysis and proceed to the definition of the sample size of the main experiment (see "Statistic plan").
scRNA-Seq libraries will be generated by Chromium Single Cell 3' Reagent Kit and Chromium Controller (10X Genomics). Samples with more than 90% of viable cells will be chosen for further analysis. For reaction, approximately 10,000 living cells per sample will be loaded for the generation of gel bead-in-emulsion (GEM). The released RNA from each captured cell in individual GEM will be barcoded by reverse transcription. The barcoded cDNAs will be pooled and cleaned. The cDNAs will be further amplified and sequenced on Illumina NextSeq 550. We will perform paired-end scRNA-Seq to identify and quantify differential gene expression patterns. We will apply appropriate pipeline from the 10X Cell Ranger suite.
Computational analyses performed exploiting, among the others, Seurat package will be useful to reveal critical gene networks, and molecular pathways associated with fibrosis at single cell level. In addition, a computational dissection of the "Liver Fibrosis" evolutionary trajectories will be performed by deconvolution approaches (see "Methods of data collection"). Differentially expressed transcripts will be selected based on the availability of specific antibodies for immunohistochemistry (IHC), IF and Western blotting (WB), and validated by qRT-PCR and biochemical studies. Selected markers will be validated in Aim 3.
Experimental design aim 2
Generation of a liver-specific HIPK2 knockout mouse model to establish the contribution of HIPK2 in liver fibrosis.
To directly explore the anti-fibrotic activity of targeting the pro-fibrotic kinase HIPK2 in the liver, we are already generating liver-specific HIPK2 knockout (HIPK2-LKO) mice, which will be compared with the wild-type HIPK2 controls (HIPK2-WT) before and after induction of liver fibrosis.
We have previously obtained C57BL/6 mice carrying an HIPK2 knockout-first (KOF) allele cassette with conditional potential (9). Part of this cassette is flanked by FRT sites and removable by FLP recombinase activity. Thus, we have
generated the HIPK2cKO/cKO mice by crossing HIPK2 KOF mice with transgenic mice ubiquitously expressing the FLP recombinase. Since exons 3 and 4 of HIPK2 are flanked by LoxP sites, a further activity of CRE recombinase is required for excision of these critical HIPK2 exons and the generation of ubiquitous or tissue-specific HIPK2 knockout (HIPK2LOX/LOX) mice. In particular, HIPK2-LKO mice (i.e., liver-specific HIPK2LOX/LOX mice) will be obtained by crossing our HIPK2cKO/cKO mice (from hereon, HIPK2-WT mice) with the Albumin-Cre mice (i.e., B6.Cg-Speer6-ps1<Tg(Alb- cre)21Mgn>/J from Xxxxxxx Laboratories) (Fig. 1) (10). Occurrence of tissue-specific allele rearrangement and HIPK2 depletion will be assessed before subsequent breeding and fibrosis induction.
Both HIPK2-LKO and HIPK2-WT mice will be treated with two well-established approaches of liver fibrosis induction (Fig. 2): 1) a chemical approach, by intraperitoneal injection of carbon tetrachloride (CCl4) (11) that is metabolized in the liver and converted into a highly reactive tri-chloromethyl (CCl3) radical, ultimately leading to hepatotoxic damage, inflammation and fibrosis mimicking advanced CLD (12); 2) a diet approach, by feeding mice with a high fat choline-deficient amino-acid defined diet (HF-CDAA) that is high in fat (60%) and being deficient in choline results in a reduced clearance of triglyceride and in accumulation of lipids in the liver, mimicking non-alcoholic steatohepatitis disease (13). Of note, the ministerial authorization to perform these protocols has been already obtained (Allegato VI, Autorizzazione n°833/2021-PR).
Next, we will analyze liver tissues obtained from mice in the different experimental conditions (see Aim 3). Together with standard liver parameters including size, shape, and color, we will evaluate structural changes of hepatic tissue, hyperplasia of collagen fibers, and ECM deposition. In particular, the expression levels of pro-collagen1alpha1, collagen I, collagen III, TGF-beta1, HSP74, fibronectin, vimentin, alpha-SMA, TIMP, FAP, and Galectin-3 (14) will be evaluated by qRT-PCR, IF, IHC, and/or WB.
To gain broader view of HIPK2 role in liver fibrosis, liver transcriptomes in the different experimental conditions will be assessed by bulk RNA-Seq and, eventually, data compared with those obtained by scRNA-Seq in Aim 1. Indexed libraries will be prepared from 500 ng/each purified RNA with TruSeq Stranded total-RNA Sample Prep Kit (Illumina). Libraries will be quantified with TapeStation 4200 and Qubit fluorometer, then pooled such that each index-tagged sample will be present in equimolar amounts. Pooled samples will be subject to cluster generation and sequencing using an Illumina NextSeq 550 system in a 2x75 paired-end format. Sequencing reads will be processed by the nf-core's pipeline for RNAseq and the obtained counts will be analyzed by the appropriate R packages. Selected, differentially expressed transcripts will be validated by qRT-PCR and, when specific antibodies are available, by IF or IHC. Finally, in addition to the functional characterization of HIPK2 silencing response in mice, the signatures will be compared with available gene sets. Particular attention will be paid to metabolic dysfunction that might be detected via transcriptomics signatures (see "Methods of data collection").
Experimental design aim 3
Pilot validation of HIPK2 and new emerging biomarkers of liver fibrosis. HIPK2
If, as hypothesized, HIPK2 LKO mice are resistant to liver-fibrosis induction, we will employ HIPK2 inhibitors, such as those we have preliminary tested in Figures 4-6, to explore their anti-fibrotic activity on hLSCs and on HIPK2-WT mice fed with the pro-fibrotic diet. For the experiments with hSCLs, we will inhibit HIPK2 activity by XXXX (00) and by abemaciclib (16) in the presence or absence of TGF-beta1 and assess fibrosis as described in Aim 2. For animal experiments, HIPK2 WT mice will be fed with: i) control diet, ii) pro-fibrotic CDAA diet for 21 weeks, or iii) pro-fibrotic HF-CDAA diet in the presence of the HIPK2 inhibitor abemaciclib. Liver transcriptomes will be assessed by bulk RNA-Seq as described in Aim 2.
New biomarkers
To validate the potential role of HIPK2 in the development of liver fibrosis and to test potential new biomarkers identified in Aims 1 and 2, UO3 and UO4 will collect a large series of clinically annotated retrospective samples from liver biopsies and surgical specimens. To explore correlations with liver fibrosis development and progression, hepatocellular carcinoma (HCC) and/or cholangiocarcinoma development and prognosis, and (potentially) with metastatic competence, five different series of samples will be analyzed, to encompass different liver conditions:
1. normal liver from elective cholecystectomy (UO4: 100 cases);
2. liver biopsies from non-cancer patients affected by XXXX (UO4: 50 cases);
3. HCC resection specimens (UO3: 20 cases; UO4: 80 cases); moreover, through the collaboration with the Verona Liver Transplant Center, approximately 100 entire livers from patients undergoing liver transplant for end-stage cirrhosis and/or HCC will be made available to the study.
4. cholangiocarcinoma resection specimens (UO3: 20 cases);
5. liver tissue surrounding or distant from metastases of colorectal and pancreatic cancers (UO3: 50 cases; UO4: 100 cases).
Depending on the biomarker to be studied, IHC and/or molecular techniques will be employed to assess the biomarker(s) of interest. In particular, in order to analyze the tissue distribution of the biomarker(s) of interest and the contribution of different cellular populations (hepatocytes, HSC, specific infiltrating immune populations), we will employ multiplex IHC (mIHC): briefly, mIHC will be performed by staining with 4 and up to 8 primary antibodies, targeting the biomarker(s) and cellular subpopulations of interest and allowing to dissect their cell of origin and spatial distribution; in selected cases, mIHC will be complemented by RNA in situ hybridization, in order to define which microenvironmental component/s express the specific biomarkers of interest.
In a subset of cases from sample groups 2 and 3, available imaging data (including non-invasive liver fibrosis assessment, MRI, CT scans) will be retrieved and analyzed in context with pathological and molecular data; radiomic features will be extracted, analyzed using machine learning and artificial intelligence-based techniques and exploratorily correlated with molecular endpoints.
Pathological, molecular, imaging, and clinical data will be collected in a pseudonymized form in a dedicated, web-based database, developed by the participating clinical units using the Redcap platform (xxxxx://xxx.xxxxxxx-xxxxxx.xxx/).
UOs will adopt appropriate technical and organizational measures to guarantee an adequate level of security of the data and samples processed in the study, as well as specific and technical measures to increase the same and to prevent the dissemination of personal data or their use by unauthorized parties (see "Methods of data collection").
Picture to support preliminary data
Soddu Fig.1-6.pdf
Hypothesis and significance
Non-alcoholic fatty liver disease has reached global epidemic proportion becoming the most cause of CLDs. CLD progression toward cirrhosis and hepatocellular carcinoma is linked to necroinflammation and liver fibrosis. However, the molecular determinants of these events are still unclear and candidate biomarkers for prevention and treatment are under intense investigation. We hypothesize that a successful identification of candidate biomarkers for liver fibrosis cannot disregard the evaluation of the entire hepatic microenvironment. Traditional preclinical platforms, including 3D organoid cell cultures and their xenografts, take into account specific cell populations but do not consider the real complexity of the tissue environment. Instead, studies comparing liver biopsies are limited by the long and non-homogenous evolution of the disease. Here, we propose to overcome these limitations by performing omics-analyses on organotypic slice cultures obtained by cutting fresh human livers from patients that undergo liver surgery for metastatic disease or other pathologies. These hLSCs will be treated in vitro with anti- and pro-fibrotic agents and analyzed in the following week by time-lapse, multiple immune fluorescence for known fibrosis pathways, single-cell-sequencing or bulk RNAseq. This type of analyses will be combined with a hypothesis-driven strategy based on the generation and study of a liver specific HIPK2 KO mouse model. We expect to identify actionable targets and strategies for the prevention and treatment of liver fibrosis.
5.5 Methodologies and statistical analyses
Methods of data collection
Single-cell-sequencing
The preliminary statistics of the sequencing quality will be performed using Illumina Sequencing Analysis Viewer. We will implement the 10X workflow for multiple samples processed through multiple GEM xxxxx, generating multiple libraries and
eventually onto one flow cell. The workflow will start by demultiplexing the Illumina sequencer's base call files (BCLs) for each flow cell into FASTQ files using a wrap of Illumina bcl2fastq called "cellranger mkfastq" (10x genomics software). After demultiplexing, "cellranger count" will run separately for each GEM well performing alignment [with STAR (17)], filtering, barcode counting, and UMI counting then it will generate feature-barcode matrices, determine clusters, and will perform gene expression analysis. Finally, "cellranger aggr" will aggregate all the samples generating feature-barcode matrices, determining clusters, and performing gene expression analysis. We use the human genome (GRCh38) as reference. The Cell Ranger pipeline will also produce quality control reports and a first analysis for each sample and for the whole experiment. To display the most important cell features, gene expression matrix will be reduced by Cell Ranger via Principal Components Analysis (PCA) and then clustered by Cell Ranger via k-means algorithm with default parameters. The cell subpopulations will be visualized in two-dimensional images by t-Stochastic Neighbor Embedding (t-SNE) plot. More in- depth analysis will be performed using Seurat pipeline (18) and custom in-house scripts on R software (19). Custom in- house scripts will be used for further investigations on identifying novel cellular states.
Computational dissection of "Liver Fibrosis" evolutionary trajectories
To understand the molecular and evolutionary processes underlying fibrosis development, we will design a computational workflow exploiting primary and secondary analysis modeling of all the omics data produced during the project. Several deconvolution approaches will be applied to describe the hepatic microenvironment of hLSCs and provide a fine-grained comparison of mentioned models against known available human transcriptomics data (20, 21). An evolutionary lineage from hLSCs to known single-cells profiles of human livers will be produced.
For functional characterization of HIPK2 silencing response, signatures will be compared with available gene sets employed in commercial panels and further characterized using available data from high-throughput CRISPR screens (22). The last step will shear light on co-lethality of said signatures with HIPK2 in liver and adjacent tissues. Specific attention will be paid to metabolic dysfunction that could be early detected via transcriptomics signatures. We will mine the literature for genes coding for known metabolites and we will curate a panel of putative metabolic signatures that will be tested a-priori on all the profiled samples in vivo and ex-vivo. This unsupervised approach will be coupled with a supervised one, in which signatures showing to be differentially modulated in fibrosis and treated clusters will be functionally described via enrichment algorithms (23, 24) and gene sets profiles (25) to understand whether specific metabolites are more enriched in particular conditions.
A web portal describing the fibrotic liver atlas will be designed, implemented and deployed towards the end of the project, split in two sections, one for researchers and computational biologists, another for the general public to inform and educate about liver fibrosis.
Pilot validation
For security, access to computer systems will be made possible only for authorized personnel. Data, material and documentation will be kept for a time not exceeding that necessary to achieve the purposes of the study, for scientific research purposes related to the project, and to what is established by the legislation and by the regulations governing the matter.
Statistic plan
Single-cell-sequencing
To define a statistically meaningful number of samples to be tested, we will first determine the minimum magnitude and FC (effect size) of the gene expression and the smallest cell population we are interested in. According to Xxxxxx (26), to choose the optimal parameter combination of sample size, cells per sample, and read depth for an experimental design, we will build a scRNA-Seq pilot experiment on hLSCs with 10k cells/sample, 10k reads/sample, and the smallest testable cell type being the 15% of the cells/sample. Given these parameters and exploiting the expression distribution fit of data set available in the scPower package (27), we need 12 samples to obtain an overall power of 0.7. The pilot study foresees a t0 control (t0_CNTL), t1 control (t1_CNTL), a t1 (7 days) upon TGF-beta-induced fibrosis (t1_TGFb). In addition to obtaining
the preliminary data for the power analysis and subsequent definition of the sample size, if we will observe no significant difference between t0_CNTL and t1_CNTL, t0_CNTL will be removed from the main experiment. This pilot study will allow us to define: i) the percentage of cells of the smallest (experiment wise) cell type in order to define the wanted cell per sample and ii) the number of detected and differentially-expressed genes to define the read depth.
Animal study
As for the model of kidney fibrosis in which the absence of HIPK2 reduces collagen levels (3), we expect a significant reduction of collagen in all the HIPK2-LKO animals treated with CCl4 or HF-CDAA compared to their related controls. Assuming that a significant increase of collagen levels will be observed in 100% of the HIPK2-WT animals treated with pro- fibrotic compounds vs a conservative percentage of 60% of animals in the HIPK2-LKO corresponding group, we will need 30 mice (15 each, considering a 1:1 ratio) to observe a difference of 40% with a first type error equal to 5% and a power of 80%. Animals in control groups will be evaluated to assess collagen basal expression. To reduce the number of animals included in the experimentation (3Rs principles) we will use only 5 animals for each control group. In summary, for both experimental protocols, two groups of 20 animals for each line (i.e., 20 HIPK2-WT and 20 HIPK2-LKO mice) will be randomly divided in two subgroups with a 3:1 ratio: 15 animals will be treated for fibrosis induction (CCl4 or HF-CDAA) whereas 5 animals will be treated with the vehicle or control diet to assess the basal level of fibrosis markers expression.
Bulk RNA-Seq
We set our work as a pilot trial with the aim to define the correct standardized effect and sample size for a subsequent main trial together with preliminary biological characterization. According to (28), with a standardized effect greater than 0.7 (Xxxxx effect size) and 80% powered main trial, the size of each arm of the pilot trial should be around 10 samples. Thus, we expect to process 30 livers from the following WT mice: 10 feed with the control diet, 10 with the pro-fibrotic diet, and 10 with the pro-fibrotic diet in the presence of HIPK2 inhibitor. The nf-core/rnaseq pipeline [version 3.6 (29)] written in the Nextflow domain specific language [version 19.10.0 (30)] will be used to perform the primary analysis of the samples in conjunction with Docker (31). In short, the quality of the raw reads will be evaluated, the 5' and 3' adapters will be trimmed, genome/ribosomal RNA sequences will be discarded. Secondly, the filtered reads will be aligned to reference genome sort, indexed, marked for duplicate, and gene/transcript quantified. A regression-like model implemented by edgeR package (32) will be used for differential gene expression analysis among experimental conditions. Xxxx sets overrepresentation for each differential expressed gene list will be produced applying ClusterProfiler (33) and GSEA package. Statistical analysis will be performed using the computing environment R.
Statistical analysis
Statistical analysis will be performed using SPSS software 23.0 version (v. 21.0, SPSS Inc., Chicago, IL, USA). Categorical data will be reported as frequencies and percentages or intervals for quantitative variables, and data will be compared using the Chi-squared test or Xxxxxx exact test, when appropriate, for continuous data, mean ± standard deviation and median (range). Comparisons between groups with continuous data will be performed using the ANOVA test or the Xxxxxxx-Wallis test, as appropriate. Correlations between continuous variables will be assessed using Xxxxxxxx'x rank correlation coefficient analysis or the correlation coefficient Xxxxxxx will be calculated. Survival curves will be calculated by the Xxxxxx-Xxxxx product limit method from the date of the surgery until relapse/progression or death. The log-rank and Tarone-Ware tests will be used to assess differences between subgroups. The level of significance will be set at p minor/equal to 0.05.
Timing of analysis data
Fresh human liver samples to generate hLSCs will be collected during the entire duration of the study. We expect to collect 100 liver punch biopsies in two years. From each biopsy we will obtain 20/25 slices.
The pilot study for scRNA-Seq will be performed within the first 4 months of the project. scRNA-Seq experiments will be performed within the first year of the project.
Computational analyses of scRNA-Seq data will be performed at the end of the first year while the computational dissection of Liver Fibrosis evolutionary trajectories will be performed during the second year.
HIPK2 LKO mice will be available for the beginning of the project. They will be treated for fibrosis-induction since month one. Biochemical and genetic evaluation of mice livers will be performed through the first year. Transcriptomic studies will be performed during the second year of the project.
Validation studies on human liver biopsies will be performed during the second year.
5.6 Expected outcomes
- Establish human liver slice cultures as preclinical platform to explore pathological fibrosis processes and screen for new biomarkers and/or therapeutic approaches
- Identify novel putative liver fibrosis gene signatures and biomarkers
- Identify HIPK2 functions in liver fibrosis
- Validate HIPK2 as perspective target for prevention/treatment of liver fibrosis
5.7 Risk analysis, possible problems and solutions
Human organotypic slice cultures have been successfully obtained and applied from different human cancers.
Liver fibrosis in vivo is a long process. We will have 7/8 days in culture to induce hepatic stellate cell (HSC) activation into myofibroblasts and subsequent deposition of EMC. TGF-beta1 has been shown to potently activate HSC in 2D/3D cultures in 3/4 days. Thus, we expect to obtain significant activation also in hLSCs. If we do not gain sufficient fibrosis induction, we will bust TGF-beta1 effects by macromolecular crowding with different compounds (8).
As shown in Figures 4-6, HIPK2 inactivation can be obtained in culture using different strategies. Thus, we will have the possibility to employ these or additional compounds (15) to inhibit HIPK2 activity both in hLSCs and in HIPK2 WT animals. Regarding induction of fibrosis in mice, the experimental protocols and time points have been opportunely chosen on the basis of extensive literature data available and the experimental design has been structured in order to answer hypotheses with different approaches, increasing the chance to obtain good quality and consistent data.
We are aware of the possible biases introduced by the retrospective design adopted for validation studies. Such choice is justified by the need for a follow up time long enough to capture fibrosis evolution over time and, possibly, development of primary liver cancer or liver metastases. Indeed, the retrospective sample series collected will span a period of at least 10 years, thereby allowing to draw conclusions on clinical correlations within the project's timeframe. However, should solid potential biomarker(s) be identified early on in the preclinical phase of the project or show strong predictive power and correlation with intermediate fibrosis-related endpoints in the retrospective validation phase, prospective protocols aimed at collecting imaging, pathological and clinical data in patients affected by different liver diseases, currently ongoing at participating Institutions, will be amended to include prospective evaluation of candidate biomarker(s) and correlation with intermediate disease evolution endpoints.
5.8 Significance and Innovation
CLDs are becoming a global health burden; they are responsible for approximately 2 million deaths per year worldwide (34). However, the molecular determinants are unclear and the main drug treatment strategies for liver fibrosis are still based on elimination of the primary noxa and control of inflammation. Thus, candidate biomarkers for prevention and treatment are under intense investigation. The novelty of this project resides in the preclinical human liver model (i.e., hLSCs) we will employ for spatial transcriptomic analyses. Compared with traditional preclinical platforms, hLSCs have the advantage of maintaining the morphology and microenvironment of the host tissue, and allow the investigation of spatial dynamics, drug delivery, stromal and immune responses. In addition, we will take advantage of our strong expertise in the biology of HIPK2 to explore the anti-fibrotic activity of its targeting in both liver-specific HIPK2 KO mice and hLSCs.
5.9 Bibliography
(1) Methods in Mol Biol 2019, xxx.xxx/00.0000/000-0-0000-0000-0_00 (2) J Mol Med 2013, doi: 10.1007/s00109-013-1042-0
(3) Nat Med 2012, doi: 10.1038/nm.2685
(4) Biomed & Pharmacother 2017, doi: 10.1016/j.biopha.0000.00.000
(5) Nat Cell Biol 2001, doi: 10.1038/ncb714
(6) Nat Commun 2019 doi: 10.1038/s41467-018-07858-8
(7) Clin Cancer Res 2019 doi: 10.1158/1078-0432.CCR-19-0081
(8) Frontiers in Medicine 2021, doi: 10.3389/fmed.2020.615774 (9) Nature 2011, doi: 10.1038/nature10163
(10) Hepatogy 2015, doi: 10.1002/hep.27659
(11) Int J Stroke 2009, xxx.xxx/00.0000/x.xxxx.0000.00.000
(12) Critical Rev Toxicol 2003 xxx.xxx/00.0000/000000000
(13) Int J Exp Pathol 2013, doi: 10.1111/iep.12008
(14) Toxicology in Vitro 2007, doi: 10.1016/j.tiv.2006.12.009 (15) Protein Sci 2018, doi: 10.1002/pro.3367
(16) Xxx Xxxxxx 2021, doi: 10.1038/s41467-021-26935-z
(17) Bioinformatics 2013, doi: 10.1093/bioinformatics/bts635 (18) Cell 2021, xxx.xxx/00.0000/x.xxxx.0000.00.000
(19) R Core Team 2021, xxxxx://xxx.X-xxxxxxx.xxx/
(20) J Transl Med 2019, doi: 10.1186/s12967-019-1865-8
(21) J ImmunoTher Cancer 2022, xxx.xxx/00.0000/xxxx-0000-000000 (22) Cancers 2019, xxx.xxx/00.0000/xxxxxxx00000000
(23) bioRxiv 2022, xxx.xxx/00.0000/0000.00.00.000000
(24) Nucl Acids Res 2016, doi: 10.1093/nar/gkw377
(25) Proc Nat Aca Sci USA 2005, doi: 10.1073/pnas.0506580102 (26) Xxx Xxxxxx 2021, xxx.xxx/00.0000/x00000-000-00000-0
(27) Xxxx.xx 2022, xxxxx://xxxx.xx/xxxxxx/xxxxxxxxx/xxXxxxx/
(28) Stat Methods Med Res, 2016, doi: 10.1177/0962280215588241 (29) Nat Biotechnol 2020, xxx.xxx/00.0000/x00000-000-0000-x
(30) Nat Biotechnol 2017, xxx.xxx/00.0000/xxx.0000
(31) Semantic Scholar 2014, xxxxx://xxx.xxxxxxxxxxxxxxx.xxx/xxxxxx/Xxxx-Xxxxxx/00000000
(32) Nucl Acids Res 2012, doi:10.1093/nar/gks042 (33) OMICS 2012, doi: 10.1089/omi.2011.0118
(34) X Xxxxxxx 2019, doi: 10.1016/j.jhep.2018.09.014
5.10 Timeline / Deliverables / Payable Milestones
- Definition of protocol/s for the generation of organotypic slice cultures by human livers (open)
- HIPK2 LKO mice
- A collection of mouse liver samples after fibrosis induction in presence or absence of HIPK2
- Primary Analysis of at least 100 samples of single-cell and bulk RNA-seq on hLSCs and mouse livers
- List of all the putative fibrosis gene signatures found after -omics secondary analysis
- Computational Web Atlas of liver fibrosis (controlled access)
- General public Web Atlas of liver fibrosis (open)
- Novel biomarkers of liver fibrosis (open)
Milestones 12 month
- Establish organotypic slice cultures from human livers
- Define the best time and culture conditions of hLSCs to perform the omics-characterization
- Pilot study to define a statistically meaningful number of samples to be tested by single-cell-sequencing
- Generation and validation of HIPK2 LKO mice
- Induction of liver fibrosis in HIPK2 WT and HIPK2 LKO mice
- Collection of retrospective clinical samples and HIPK2 analysis by qRT-PCR
Milestones 24 month
- Collection and analyses of single-cell-sequencing data
- Characterization of livers from HIPK2 WT and HIPK2 LKO before and after induction of liver fibrosis
- Bulk RNA-Seq on mouse livers
- Computational dissection of "Liver Fibrosis" evolutionary trajectories
- Pilot validation of new emerging biomarkers of liver fibrosis on retrospective clinical samples
- Design of a web portal describing the fibrotic liver atlas
Gantt chart
Gantt chart liver fibrosis.pdf
5.11 Equipment and resources available
Facilities Available
IRE laboratories of UO1 have common spaces fully equipped to perform cell culture, biochemistry, and molecular biology. Facilities/Equipment relevant to this project are: Plate reader for proliferation and viability assay (Biotek Sinergy LX), Microscopy facility with wide-field automated microscope (Nikon Eclipse Ti2), confocal microscopes (Zeiss LSM880 with airyscan), live-cell imaging (Sartorius IncuCyte S3), and analysis software, Cytofluorometers, cell sorting facilities (BD Flow cytometer), Animal facility with surgery unit and imaging system (IVIS Lumina). At IRE is present an Oncological Biobank for Research Purposes (BBIRE), with the aims to collect, preserve and distribute human biological material, tissues and biological fluids, and the data associated with them in order to implement basic, clinical and translational oncological research.
The laboratories of UO2 provides high throughput analysis for large projects and single-cell level analysis, allowing the analysis of various types of samples with an increasing level of sensitivity and specificity. The team is composed of highly qualified and specialized professionals with both technical and scientific documented experience in the application of sequencing technologies in different fields of investigation. In addition, Prof. Xxxxxxx, a bioinformaticians in Prof. Merla's group, will be of support for data analysis. U02 is equipped with NextSeq 550 system (Illumina), Chromium Controller (10x Genomics), TapeStation 4150, (Agilent), Xxxxxxx RSC (Promega), Nanodrop (Implem), Qbit (Invitrogen), VeritiPro PCR (AB), centrifuges, thermomixers and other small bench instruments. The computational equipment includes two multi-core workstations and dedicated computational power and disk storage on the University's Central Computational Facility. UO2 covers state-of-the-art and innovative services in Genomics, Transcriptomics, Xxxxxxxxxxx, and Metagenomics fields of research. The types of provided assays include whole-genome sequencing, exome sequencing, NGS customized panel, gene expression profiling, DNA methylation (Epic Arrays), single-cell gene expression profiling, single-cell immune profiling, single-cell ATAC, single-cell immune profiling + ATAC, targeted gene expression.
Subcontract
N/A
5.12 Desc. of the complementarity and sinergy of secondary collab. researchers
The identification, validation and application of biomarkers is challenging, with several aspects, including understanding of
the biology of the biomarker and its relevance to disease, that requires different expertise. The research team organized for this project synergizes such expertise and is the logic consequence of a long-standing collaboration among at least some of the research groups. In particular, the PI, Dr Xxxxx, is among the first and most active researchers who identify HIPK2 and studied its biochemical and functional activities in physiology and tumorigenesis. Dr. Xxxxxxx, the young investigator, discovered a role of HIPK2 deficiency in the induction of CIN and is developing the HIPK2 LKO GEMM together with the coPI (Fig. 2). The co-PI, Dr. Piaggio, is a brilliant expert of transgenic animal models at the Regina Elena National Cancer Institute IRCCS (IRE). Her research focuses on transcriptional regulation of gene expression in cancer cell proliferation.
She has developed the MITO-luc mouse and zebrafish models. She is setting up the use of vibratome to cut slices of mouse tissues, such as those shown in Figure 3. This group of basic and translational researcher will directly collaborate with Prof. Xxxxx, the director of the Hepato-Pancreato-Biliary Surgical Unit at IRE, with an outstanding record of clinical and research publications. Together with the tissue bank of the same Institute, the team of UO1 will establish human liver slice cultures as well as the HIPK2 LKO GEMM. The group of clinicians includes Xxxx Xxxxxxx, head of UO4 and Dr Xxxxx, head of UO3. Xxxx Xxxxxxx is an excellent medical oncologist and an expert in discovery, development and clinical experimentation of new anticancer and molecularly targeted drugs. In this field he has made a substantial contribution to the identification and analysis of molecular biomarkers as predictors of response to therapy. Dr Xxxxx is an excellent medical oncologist and an expert in metastatic disease of abdominal cancers. In this field he has made a substantial contribution to radiomics, molecular characterization, and innovative therapeutic strategies for rare malignant tumors of the digestive tract. Since liver slices have to be freshly prepared by the researchers, UO3 and UO4 will be involved in the study after the setting up of the procedures that will be eventually exported to these two Institutes. Besides that, UO3 and UO4 will be in charge of performing pilot validation of HIPK2 and new emerging biomarkers of liver fibrosis on their retrospective cohorts of liver samples. Finally, omics-characterization of hLSCs will be performed by Prof. Xxxxx, the head of UO2, together with two young brilliant assistants to hire, Drs. Xxxxx and Xxxxxxxxx, one of which has already shown to be a very productive collaborator. Merla's group has developed skills and expertise in the implementation of omics techniques such as transcriptomics (bulk RNAseq and scRNAseq), ChiPSeq, and proteomics for medical genetics and oncology research projects. Within the project framework, he will direct and supervise the entire omics workflow of the proposal. Finally, Dr Xxxxxxxx (UO1), a very brilliant young computer scientist at IRE, whose main research interests are result reproducibility, biomarker discovery, and validation from omics data, will be in charge for omics data analyses.
5.13 Translational relevance and impact for the national health system (SSN)
What is already know about this topic?
In the clinical practice, liver biopsy associated with several scoring systems for risk stratification are currently used for accurate staging of the degree of liver injury and specific treatment decisions. However, liver biopsy is an invasive procedure that carries the risk of morbidity and mortality, and its prognostic value is still limited. In the past decade, several non-invasive tests for liver fibrosis, such as the Enhanced Liver Fibrosis test, the FibroTest, the FibroMAX, and transient elastography FibroScan® have been developed. However, their diagnostic accuracy, cost- effectiveness, and effect on patient outcomes are still debated. Thus, identification of new candidate prognostic biomarkers is a major objective in the current research.
Details on what is already know about this topic
CLDs are becoming a global health burden; they are responsible for approximately 2 million deaths per year worldwide, with approximately 1 million deaths resulting from complications associated with cirrhosis. At present, the main drug treatment strategies for fibrosis are still based on elimination of the primary noxa, control of inflammation, improvement in liver parenchyma cell injury. Despite this high unmet clinical need, only two anti-fibrotic drugs, Pirfenidone/Esbriet® and Nintedanib/Ofev® have been approved to date. Moreover, these agents slow rather than halt disease progression.
- Xxxxxxxxx X and Kutala BK. Liver diseases: a major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int. 2018. doi: 10.1111/liv.13682
- Xxxxxxxxxx D, et al. Current and future pharmacological therapies for managing cirrhosis and its complications. World J Gastroenterol. 2019. doi: 10.3748/wjg.v25.i8.888
What this reasearch adds?
This project will i) define the causal role of HIPK2 in liver fibrosis and the possible use of its inhibitors as anti-fibrotic therapies; ii) define the use of organotypic slice cultures as more physiological preclinical platforms to exploit microenvironment determinants that include stromal and immune cells; iii) identify novel biomarkers, in addition to HIPK2, for liver fibrosis prevention and treatment
Details on what this reasearch adds
Given the lack of reliable, disease-elevant in vivo models of fibroproliferative diseases, anti-fibrotic drug discovery relies heavily on phenotypic in vitro models. Despite advancement of disease-relevant 3D cell culture models, there is still a clear need for in vitro models of fibrosis which evaluate the contribution of stromal and immune microenvironment.
As indicated above, our study will provide such new in vitro model directly based on human liver slice cultures in which fibrosis can be induced and studied in culture.
- Good RB, et al. A high content, phenotypic 'scar-in-a-jar' assay for rapid quantification of collagen fibrillogenesis using disease-derived pulmonary fibroblasts. BMC Biomed Eng. 2019. doi: 10.1186/s42490-019-0014-z
- Bigaeva E, et al. Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis. Pharmaceutics. 2020. doi: 10.3390/pharmaceutics12050459
What are the implications for public health, clinical practice, patient care?
This proposal has the likelihood of identifying novel biomarker(s) for liver fibrosis prevention and treatment. This will pave the way of next clinical evaluation to validate the use of the identified biomarker(s) in different CDLs, to predict progression into cirrhosis, hepatocellular cancer, and/or induction of metastasis-permissive liver. In addition, it opens the possibility of evaluating whether the biomarker(s) might be targets for anti-fibrotic therapies.
Details on what are the implications for public health, clinical practice, patient care
Hopefully, novel fibrosis biomarkers and therapies will improve the management of CLDs and reduce the increasing burden of liver cirrhosis and its associated pathological processes.
6 - Budget
Total proposed budget ( Euro ) | ||||
Costs | TOTAL BUDGET | Co-Funding | List of costs proposed for funding to the MOH | Percentage of total proposed to the MOH |
1 Staff Salary | 327.000,00 | 327.000,00 | not permitted | 0,00 |
2 Researchers' Contracts | 310.000,00 | 0,00 | 310.000,00 | 31,00 |
3a.1 Equipment (Leasing - | 84.000,00 | 28.000,00 | 56.000,00 | 5,60 |
3a.2 Equipment (buying) | 0,00 | 0,00 | 0,00 | 0,00 |
3b Supplies | 410.000,00 | 0,00 | 410.000,00 | 41,00 |
3c Model Costs | 25.000,00 | 10.000,00 | 15.000,00 | 1,50 |
4 Subcontracts * | 0,00 | 0,00 | 0,00 | 0,00 |
5 Patient Costs | 0,00 | 0,00 | 0,00 | 0,00 |
6 IT Services and Data Bases | 39.000,00 | 0,00 | 39.000,00 | 3,90 |
7 Travels | 20.000,00 | 0,00 | 20.000,00 | 2,00 |
8 Publication Costs | 30.500,00 | 0,00 | 30.500,00 | 3,05 |
9 Dissemination | 19.500,00 | 0,00 | 19.500,00 | 1,95 |
10 Overheads * | 70.000,00 | 0,00 | 70.000,00 | 7,00 |
11 Coordination Costs | 30.000,00 | 0,00 | 30.000,00 | 3,00 |
Total | 1.365.000,00 | 365.000,00 | 1.000.000,00 | 100,00 |
* percentage calculated as average value between all the Operating Units.
Report the Co-Funding Contributor:
staff salary is provided by the utilized % in the project of the permanent salaries of the scientists. UO1: Xxxxxx Xxxxx (40%), Xxxxxx Xxxxxxx (25%), Xxxxxx Xxxxxxxx (25%), Xxxxxx Xxxxxxx (75%), XxxxXxxx Xxxxx (20%). UO2: Xxxxxxxx Xxxxx (30%)
Budget Justification | |
1 Staff Salary | Staff salary is provided by the utilized % in the project of some of the permanent salaries of the scientists. |
2 Researchers' Contracts | 2 biennal research contracts for under 40 researcher. 1 biennal fellowship for a computational biologist. 1 biennal fellowship for a data manager. 1 biennal research contract |
3a.1 Equipment (Leasing - Rent) | N.A. |
3a.2 Equipment (buying) | N.A. |
3b Supplies | Kit for scRNASeq, bulk RNASeq, RTPCR reagents, DNA and RNA extraction Kits, drugs, antibodies, IHC kits, cell culture plasticwares, organoid slice culture and digital pathology kits, mIHC, RNA ISH/transcriptomics, supplies for genetic assessments |
3c Model Costs | Animal housing and breeding. We will use around 300 animals, a mean of 150 mice/year=38 cage/year (4 mice a cage), 130 euro cage/year. We need choline-deficient, L-amino acid-defined (CDAA) diet. |
4 Subcontracts | N.A. |
5 Patient Costs | N.A. |
6 IT Services and Data Bases | Storage extension for approximately 10 Terabytes of data of all the -omics analyses, considering 100GB of primary and secondary data. Computing costs for single-cell bioinformatic analyses on a 256GB RAM/64 CPU server. Clinical DB development. |
7 Travels | Travel costs for meeting and congress participation and seminars upon invitation |
8 Publication Costs | publication cost for 3/4 publications on open access journals per year |
9 Dissemination | Fee for 1 national and 1 international congresses per year per Unit to disseminate results. |
10 Overheads | To cover Institutional expenses for instrument maintenance and administrative costs |
11 Coordination Costs | At least two meetings among the Units during the project. Exchange of visiting fellow among different institutes. Transportation between different institute of biological materials. |
Proposed total budget UO1 Institution: Istituti fisioterapici ospitalieri - Istituto Regina Elena (Euro)
Costs | TOTAL BUDGET | Co-Funding | List of costs proposed for funding to the MOH | Percentage of total proposed to the MOH |
1 Staff Salary | 287.000,00 | 287.000,00 | not permitted | 0,00 |
2 Researchers' Contracts | 50.000,00 | 0,00 | 50.000,00 | 12,50 |
3a.1 Equipment (Leasing - Rent) | 0,00 | 0,00 | 0,00 | 0,00 |
3a.2 Equipment (buying) | 0,00 | 0,00 | 0,00 | 0,00 |
3b Supplies | 203.000,00 | 0,00 | 203.000,00 | 50,75 |
3c Model Costs | 25.000,00 | 10.000,00 | 15.000,00 | 3,75 |
4 Subcontracts | 0,00 | 0,00 | 0,00 | 0,00 |
5 Patient Costs | 0,00 | 0,00 | 0,00 | 0,00 |
6 IT Services and Data Bases | 30.000,00 | 0,00 | 30.000,00 | 7,50 |
7 Travels | 12.000,00 | 0,00 | 12.000,00 | 3,00 |
8 Publication Costs | 20.000,00 | 0,00 | 20.000,00 | 5,00 |
9 Dissemination | 12.000,00 | 0,00 | 12.000,00 | 3,00 |
10 Overheads | 28.000,00 | 0,00 | 28.000,00 | 7,00 |
11 Coordination Costs | 30.000,00 | 0,00 | 30.000,00 | 7,50 |
Total | 697.000,00 | 297.000,00 | 400.000,00 | 100,00 |
Budget Justification | |
1 Staff Salary | staff salary is provided by the utilized % in the project of the permanent salaries of the scientists: Xxxxxx Xxxxx (40%), Xxxxxx Xxxxxxx (25%), Xxxxxx Xxxxxxxx (25%), Xxxxxx Xxxxxxx (75%), XxxxXxxx Xxxxx (20%). |
2 Researchers' Contracts | One biennial computational biologist fellowship for the duration of the whole project |
3a.1 Equipment (Leasing - Rent) | N.A. |
3a.2 Equipment (buying) | N.A. |
3b Supplies | Reagents for molecular biology experiments. RT-PCR reagents, DNA extraction Kits, RNA extraction Kits, drugs, antibodies, IHC kits, cell culture costs, organotypic slice cultures and digital pathology kits (around 1000 slices are planned) |
3c Model Costs | Animal housing and breeding. We will use around 300 animals, a mean of 150 mice/year=38 cage/year (4 mice a cage), 130 euro cage/year. We need choline-deficient, L-amino acid-defined (CDAA) diet. |
4 Subcontracts | N.A. |
5 Patient Costs | N.A. |
6 IT Services and Data Bases | Storage extension for approximately 10 Terabytes of data of all the -omics analyses, considering 100GB of primary and secondary data for approximately 100 samples. Computing costs for single-cell bioinformatic analyses on a 256GB RAM/64 CPU server. |
7 Travels | Travel costs for meeting and congress participation and travel cost upon invitation |
8 Publication Costs | Publication cost for 1/2 publications on open access journals per year. |
9 Dissemination | Fee for 1 national and 1 international congress for dissemination of results |
10 Overheads | To cover Institutional expenses for instrument maintenance and administrative costs |
11 Coordination Costs | At least two meetings among the Units during the project. Exchange of visiting fellow among different institutes. Transportation between different institute of biological materials. |
Proposed total budget UO2 Institution: University of Xxxxxx Xxxxxxxx XX (Euro)
Costs | TOTAL BUDGET | Co-Funding | List of costs proposed for funding to the MOH | Percentage of total proposed to the MOH |
1 Staff Salary | 40.000,00 | 40.000,00 | not permitted | 0,00 |
2 Researchers' Contracts | 160.000,00 | 0,00 | 160.000,00 | 40,00 |
3a.1 Equipment (Leasing - Rent) | 84.000,00 | 28.000,00 | 56.000,00 | 14,00 |
3a.2 Equipment (buying) | 0,00 | 0,00 | 0,00 | 0,00 |
3b Supplies | 140.000,00 | 0,00 | 140.000,00 | 35,00 |
3c Model Costs | 0,00 | 0,00 | 0,00 | 0,00 |
4 Subcontracts | 0,00 | 0,00 | 0,00 | 0,00 |
5 Patient Costs | 0,00 | 0,00 | 0,00 | 0,00 |
6 IT Services and Data Bases | 0,00 | 0,00 | 0,00 | 0,00 |
7 Travels | 6.000,00 | 0,00 | 6.000,00 | 1,50 |
8 Publication Costs | 6.000,00 | 0,00 | 6.000,00 | 1,50 |
9 Dissemination | 4.000,00 | 0,00 | 4.000,00 | 1,00 |
10 Overheads | 28.000,00 | 0,00 | 28.000,00 | 7,00 |
11 Coordination Costs | not permitted | not permitted | not permitted | 0,00 |
Total | 468.000,00 | 68.000,00 | 400.000,00 | 100,00 |
Budget Justification | |
1 Staff Salary | staff salary is provided by the utilized % in the project of the permanent salaries of the scientists: Xxxxxxxx Xxxxx (30%) |
2 Researchers' Contracts | 2 biennal research contracts for under 40 researcher |
3a.1 Equipment (Leasing - Rent) | Triennal leasing of Spectrum Compact CE System sequencher. Two year costs on this project. One year, cofunded |
3a.2 Equipment (buying) | N.A. |
3b Supplies | Kit and reagent for scRNASeq and bulk RNASeq. Plasticware and molecular biology reagents |
3c Model Costs | N.A. |
4 Subcontracts | N.A. |
5 Patient Costs | N.A. |
6 IT Services and Data Bases | N.A. |
7 Travels | travel fees for meeting and seminars upon invitation |
8 Publication Costs | Publication cost for 1/2 publications on open access journals per year |
9 Dissemination | Participation to 1 national and 1 international meeting per year for dissemination of results |
10 Overheads | To cover Institutional expenses for instrument maintenance and administrative costs |
11 Coordination Costs | N.A. |
Proposed total budget UO3 Institution: Istituto Nazionale Tumori IRCCS Fondazione X. Xxxxxxx (Euro)
Costs | TOTAL BUDGET | Co-Funding | List of costs proposed for funding to the MOH | Percentage of total proposed to the MOH |
1 Staff Salary | 0,00 | -0,00 | not permitted | 0,00 |
2 Researchers' Contracts | 60.000,00 | 0,00 | 60.000,00 | 60,00 |
3a.1 Equipment (Leasing - Rent) | 0,00 | 0,00 | 0,00 | 0,00 |
3a.2 Equipment (buying) | 0,00 | 0,00 | 0,00 | 0,00 |
3b Supplies | 24.000,00 | 0,00 | 24.000,00 | 24,00 |
3c Model Costs | 0,00 | 0,00 | 0,00 | 0,00 |
4 Subcontracts | 0,00 | 0,00 | 0,00 | 0,00 |
5 Patient Costs | 0,00 | 0,00 | 0,00 | 0,00 |
6 IT Services and Data Bases | 4.000,00 | 0,00 | 4.000,00 | 4,00 |
7 Travels | 1.000,00 | 0,00 | 1.000,00 | 1,00 |
8 Publication Costs | 2.000,00 | 0,00 | 2.000,00 | 2,00 |
9 Dissemination | 2.000,00 | 0,00 | 2.000,00 | 2,00 |
10 Overheads | 7.000,00 | 0,00 | 7.000,00 | 7,00 |
11 Coordination Costs | not permitted | not permitted | not permitted | 0,00 |
Total | 100.000,00 | 0,00 | 100.000,00 | 100,00 |
Budget Justification | |
1 Staff Salary | N.A. |
2 Researchers' Contracts | 1 biennal research contract (30.000 Euro/year) |
3a.1 Equipment (Leasing - Rent) | N.A. |
3a.2 Equipment (buying) | N.A. |
3b Supplies | Antibodies, IHC kits, supplies for genetic assessments |
3c Model Costs | N.A. |
4 Subcontracts | N.A. |
5 Patient Costs | N.A. |
6 IT Services and Data Bases | clinical DB development |
7 Travels | Travel costs for meeting and congresses participation |
8 Publication Costs | Publication cost for 1 publication on an open access journal per year |
9 Dissemination | Fee for 1 national and 1international congress for dissemination of results |
10 Overheads | To cover Institutional expenses for instrument maintenance and administrative costs |
11 Coordination Costs | N.A. |
Proposed total budget UO4 Institution: Verona University Hospital Trust (AOUI Verona) (Euro)
Costs | TOTAL BUDGET | Co-Funding | List of costs proposed for funding to the MOH | Percentage of total proposed to the MOH |
1 Staff Salary | 0,00 | -0,00 | not permitted | 0,00 |
2 Researchers' Contracts | 40.000,00 | 0,00 | 40.000,00 | 40,00 |
3a.1 Equipment (Leasing - Rent) | 0,00 | 0,00 | 0,00 | 0,00 |
3a.2 Equipment (buying) | 0,00 | 0,00 | 0,00 | 0,00 |
3b Supplies | 43.000,00 | 0,00 | 43.000,00 | 43,00 |
3c Model Costs | 0,00 | 0,00 | 0,00 | 0,00 |
4 Subcontracts | 0,00 | 0,00 | 0,00 | 0,00 |
5 Patient Costs | 0,00 | 0,00 | 0,00 | 0,00 |
6 IT Services and Data Bases | 5.000,00 | 0,00 | 5.000,00 | 5,00 |
7 Travels | 1.000,00 | 0,00 | 1.000,00 | 1,00 |
8 Publication Costs | 2.500,00 | 0,00 | 2.500,00 | 2,50 |
9 Dissemination | 1.500,00 | 0,00 | 1.500,00 | 1,50 |
10 Overheads | 7.000,00 | 0,00 | 7.000,00 | 7,00 |
11 Coordination Costs | not permitted | not permitted | not permitted | 0,00 |
Total | 100.000,00 | 0,00 | 100.000,00 | 100,00 |
Budget Justification | |
1 Staff Salary | N.A. |
2 Researchers' Contracts | 1 data manager for 2 yrs. 20.000€/year |
3a.1 Equipment (Leasing - Rent) | N.A. |
3a.2 Equipment (buying) | N.A. |
3b Supplies | Antibodies and reagents for IHC, mIHC, and RNA ISH/transcriptomics |
3c Model Costs | N.A. |
4 Subcontracts | N.A. |
5 Patient Costs | N.A. |
6 IT Services and Data Bases | Clinical DB development, set up and maintenance |
7 Travels | Travel costs for meeting and congresses participation |
8 Publication Costs | 2 publications in international, peer reviwed, opena access journals |
9 Dissemination | Fee for 1 national and 1 international congress to disseminate results |
10 Overheads | To cover Institutional expenses for instrument maintenance and administrative costs |
11 Coordination Costs | N.A. |
Principal Investigator Data
Cognome: SODDU Nome: XXXXXX
Genere: F
Codice fiscale: XXXXXX00X00X000X Documento: Patente, Numero: U11Y29548X Data di nascita: 26/02/1961
Luogo di nascita: Roma Provincia di nascita: RM
Indirizzo lavorativo: Xxx Xxxx Xxxxxxxx 00 Città: Roma
CAP: 00144
Provincia: RM
Email: xxxxxxxxxxx00@xxxxx.xxx Altra email: xxxxxx.xxxxx@xxx.xx Telefono: x000000000000
Altro telefono: 0000000000 Qualifica: Dirigente medico Struttura: IRCCS
Istituzione: Istituto Nazionale dei Tumori Regina Xxxxx Xxxxxx/ente di lavoro? Yes
Datore/ente di lavoro SSN? Yes Nome datore/ente di lavoro non SSN:
Nome istituzione SSN: Istituto Nazionale Tumori Regina Xxxxx IRCCS Tipo contratto: Lavoro Subordinato a Tempo Indeterminato
Con l'invio della presente proposta si dichiara che la stessa o parti significative di essa non sono oggetto di altri finanziamenti pubblici o privati e che di conseguenza vi è assenza del c.d. doppio finanziamento ai sensi dell'art. 9 del Regolamento (UE) 2021/241, ossia che non ci sia una duplicazione del finanziamento degli stessi costi da parte di altri programmi dell'Unione, nonché con risorse ordinarie da Bilancio statale.
By submitting this proposal, I declare that no significant part or parts of it are recipient of any other public or private funding and that consequently there isn't any so-called double financing pursuant to art. 9 of Regulation (EU) 2021/241, i.e. that there is no duplication in the financing of the same costs by other Euopean Union programs or any other ordinary resources from the State budget.
Project validation result
Gantt chart: Addressing liver fibrosis prevention and treatment
MILESTONES | 12 months | 24 months | ||||||||||||||||||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | |
Generation of organotypic slice cultures from human livers | ||||||||||||||||||||||||
Define the best time and culture conditions of hLSCs to perform the omics-characterization | ||||||||||||||||||||||||
Pilot study to define a statistically meaningful number of samples to be tested by single-cell- sequencing | ||||||||||||||||||||||||
Generation and validation of HIPK2 LKO mice | ||||||||||||||||||||||||
Induction of liver fibrosis in HIPK2 WT and HIPK2 LKO mice | ||||||||||||||||||||||||
Collection of retrospective clinical samples and HIPK2 analysis by qRT-PCR | ||||||||||||||||||||||||
Collection and analyses of single-cell-sequencing data | ||||||||||||||||||||||||
Characterization of livers from HIPK2 WT and HIPK2 LKO before and after induction of liver fibrosis | ||||||||||||||||||||||||
Bulk RNA-Seq on mouse livers | ||||||||||||||||||||||||
Computational dissection of “Liver Fibrosis” evolutionary trajectories | ||||||||||||||||||||||||
Pilot validation of new emerging biomarkers of liver fibrosis retrospective clinical samples | ||||||||||||||||||||||||
Design of a web portal describing the fibrotic liver atlas | ||||||||||||||||||||||||
Figure 1
Addressing liver fibrosis prevention and treatment: an unbiased query on the hepatic microenvironment with a perspective targeting of the pro-fibrotic kinase HIPK2
Critical exons
Albumin promoter
Albumin-CRE mouse HIPK2 cKO mouse
Albumin CRE transgene
X HIPK2
CRE
cKO
allele
HIPK2 LKO mouse
LoxP Sites
HIPK2 LKO allele (only in liver cells)
Schematic representation of Hipk2 liver knockout alleles: Liver specific recombinase (Albumine - CRE) expressing mice will be crossed with HIPK2 conditional knockout mice (cKO) to obtain a liver specific HIPK2 knockout mouse model (LKO).
Figure 2
Two Strategies of Fibrosis induction
-10 | 0 | 1 | 2 | 3 | 4 | 5 6 weeks |
-8 | 0 | 21 |
HIPK2-WT
HIPK2- WT and HIPK2-LKO
mice
weeks
HIPK2-LKO
IP injection of CCl4 or vehicle CDAA or control diet
Fibrosis induction procedures. Upper panel: 10 weeks old mice will be intraperitoneally injected with carbon tetrachloride (CCL4) or vehicle. Mice will be treated twice a week for 6 weeks and then sacrificed. Lower panel: 8 weeks mice will be fed for 21 weeks with a choline-deficient L- amino acid-defined diet (CDAA).
Figure 3
200 300 μm
7gg
1gg
Tissue slice cultures: Spleen was explanted from mice carrying luciferase proliferation-reporter transgene. Tissue slices were obtained using the vibratome. Slices were cultured for one week. Proliferation was assessed one or seven days after explant by using IVIS Lumina system. Luminescence signal is detectable up to one week after explant. Luciferin light emission is reported in a pseudo-color scale.
120 **
**
**
100
80
*
60
*
40
20
0
si-Ctrl si-Hipk2 si-Ctrl
SNAIL
si-Hipk2 si-Ctrl si-Hipk2 si-Ctrl si-Hipk2 si-Ctrl si-Hipk2 si-Ctrl si-Hipk2
ZEB
SLUG
TWIST1
TWIST2
VIM
mRNA expression levels
Figure 4
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
unt TGFb
Real-Time qPCR showing the reduction of Fibrosis/EMT markers in TGFβ responsive, HIPK2 depleted cells. Cells were transfected with siRNAs, treated with 5ng/ml of TGFβ as indicated and collected after 48h. Data represent Mean ± SEM of three independent experiments. *P < 0.05,
**P < 0.01 determined by t-test.
Figure 5
FGF
EGF
FBS
FGF
EGF
si-Ctrl si-HIPK2
DMSO
TBID
HIPK2 pMEK1/2 MEK1/2 pERK1/2 ERK1/2 GAPDH
-
-
FBS
-
EGF
-
EGF
1
0. 8
0. 6
0. 4
0. 2
0
pERK1/2
*
** **
**
Untr FGF EG F FBS
si-Ctrl si-HIPK2
1
0. 8
0. 6
0. 4
0. 2
0
pERK1/2
*
Untr EG F
DMSO TBID
WB analysis of HIPK2-deficient cells. HIPK2 was either depleted by siRNA or inhibited through the addition of TBID. Cells were either maintained in FBS medium (FBS) or starved in FBS-free medium (-) and then treated with either bFGF or EGF for 10 min as indicated. GAPDH was used as loading control. Histograms show densitometry data of pERK relative to control levels, normalized by GAPDH and represent Mean ± SEM of three independent experiments. *P < 0.05,
**P < 0.01 determined by t-test.
si-Ctrl
si-HIPK2
DMSO
Abem 1
Abem 5
Figure 6
Normalized Densitometry
1
0.8
0.6
0.4
0.2
0
si-Ctrl
si-HIPK2 DMSO Abem 1
HIPK2 pMEK1/2 pERK1/2 pRB SNAIL
Abem 5
HIPK2 pMEK1/2 pERK1/2
pRB SNAIL GAPDH
WB analysis showing the reduction of pMEK and pERK and SNAIL levels in HIPK2-deficient cells. HIPK2 was either depleted by siRNA or inhibited through the addition of Abemaciclib at 1μM or 5μM as indicated. pRB is used as a readout for Abemaciclib activity as CDK inhibitor. Histograms show densitometry normalized by GAPDH.