Description du projet
Cibler les ARN circulaires non codants dans le traitement de l’insuffisance cardiaque
Les principales causes de l’insuffisance cardiaque sont les processus de remodelage cardiaque au niveau moléculaire, cellulaire et tissulaire. Le projet REVERSE, financé par l’UE, étudiera l’implication de l’ARN circulaire (ARNcirc) non codant dans les lésions cardiaques associées à la cardiotoxicité induite par la chimiothérapie et à l’infection par le SARS CoV-2. De multiples signatures moléculaires d’ARNcirc non codant ont été découvertes au cours du remodelage des cellules et des tissus cardiaques chez des modèles murins et chez des personnes. Les ARNcirc non codants sont stables et conservés par les espèces, ce qui en fait des cibles idéales pour les médicaments. Le projet vise à identifier les principaux ARNcirc impliqués dans les processus de remodelage en utilisant un criblage fonctionnel de bibliothèques CRISPR-Cas et une validation dans le modèle de tissu myocardique humain. Les candidats sélectionnés seront testés dans des modèles de cardiotoxicité induite par la chimiothérapie et de maladie cardiaque induite par le SARS CoV-2.
Objectif
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.
Champ scientifique
- 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
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitution d’accueil
30625 Hannover
Allemagne