Projektbeschreibung
Zielgerichtete nicht-kodierende zirkuläre RNA in der Therapie der Herzinsuffizienz
Die Hauptursachen der Herzinsuffizienz sind kardiale Umbauprozesse auf Molekül-, Zell- und Gewebeebene. Im Rahmen des EU-finanzierten Projekts REVERSE wird untersucht, welche Rolle nicht-kodierende zirkuläre RNA (circRNA) bei Herzschäden im Zusammenhang mit Chemotherapie-induzierter Kardiotoxizität und SARS-CoV-2-Infektionen spielen. Mehrere molekulare circRNA-Signaturen wurden während der Umstrukturierung von Herzzellen und -geweben in Mäusen und Menschen entdeckt. Die nicht-kodierenden circRNA sind stabil und spezieskonserviert, was sie zu idealen Zielstrukturen für Arzneimittel macht. Das Projekt zielt darauf ab, die wichtigsten circRNA zu identifizieren, die an Umbauprozessen beteiligt sind, indem funktionelle CRISPR-Cas-Bibliotheken gescreent und im menschlichen Herzmuskelgewebe-Modell validiert werden. Die ausgewählten Kandidaten werden sowohl in Chemotherapie-induzierter Kardiotoxizität als auch in SARS CoV-2-induzierten Herzkrankheits-Modellen getestet.
Ziel
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.
Wissenschaftliches Gebiet
- 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
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
30625 Hannover
Deutschland