Descrizione del progetto
Una terapia dell’insufficienza cardiaca che prende di mira gli RNA non codificanti circolari
I processi di rimodellamento cardiaco a livello molecolare, cellulare e tissutale costituiscono le cause principali dell’insufficienza cardiaca. Il progetto REVERSE, finanziato dall’UE, approfondirà il coinvolgimento degli RNA non codificanti circolari (circRNA) nel danno cardiaco associato alla cardiotossicità indotta dalla chemioterapia e all’infezione da SARS CoV 2. Nel corso del rimodellamento delle cellule e dei tessuti cardiaci in modelli murini e umani sono state scoperte molteplici firme molecolari di circRNA. I circRNA non codificanti sono stabili e conservati a livello di specie, rappresentando bersagli farmacologici ideali. Il progetto mira a identificare i circRNA chiave coinvolti nei processi di rimodellamento mediante lo screening funzionale di librerie CRISPR-Cas e la convalida nel modello di tessuto miocardico umano. I candidati selezionati saranno testati in modelli di cardiotossicità indotta da chemioterapia e di malattia cardiaca indotta dal virus SARS CoV-2.
Obiettivo
Heart failure (HF) is a most common cause of mortality with currently >60 million of affected patients. Numbers will increase due to socioeconomic factors and as a result of the current COVID-19 pandemic. A major underlying cause of HF are cardiac remodelling processes at the molecular, cellular and tissue level. We will here focus on noncoding circular RNAs (circRNA) involved in two distinct forms of cardiac injury, chemotherapy-induced cardiotoxicity and SARS-CoV-2-infection, where currently no specific treatment strategies are available to reverse disease pathology. First proof-of-concept studies targeting the cardiac remodelling process by noncoding RNA modulation have been pioneered by us and were recently tested in a world-wide first clinical phase 1b study in HF patients. Within the family of non-coding RNAs, circRNAs are stable and species-conserved and thus ideal drug targets. We discovered multiple molecular circRNA signatures during remodelling of cardiac cells and tissues from mice and patients. We now aim to lift our research to its next inflection point with the following steps and interconnected objectives: a) discover key functional circular RNAs involved in remodelling processes by functional CRISPR-Cas library screening; b) validate circRNAs by manipulating human living beating myocardial tissue, c) explore their mode of action; and d) perform targeted cardiac delivery approaches of selected candidates in both chemotherapy-induced cardiotoxicity and SARS-CoV-2-induced cardiac disease models. A combination of bioinformatic, molecular and physiology-based methods, unique established noncoding RNA drug discovery pipelines, availability of modern S3-safety labs, large clinical biobanks and (fresh) human cardiac tissue for slicing preparations form the basis for a successful strategy. REVERSE aims to discover fundamentally new therapeutic entry points for two forms of cardiac injuries, where currently no disease-specific treatments are available.
Campo scientifico
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health scienceshealth sciencespublic healthepidemiologypandemics
- medical and health scienceshealth sciencesinfectious diseasesRNA virusescoronaviruses
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesclinical medicinecardiology
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
30625 Hannover
Germania