Descripción del proyecto
Los ARN circulares no codificantes como diana en los tratamientos para la insuficiencia cardíaca
Las principales causas de la insuficiencia cardíaca son los procesos de remodelación cardíacos a escala molecular, celular y tisular. En el proyecto REVERSE, financiado con fondos europeos, se investigará la intervención del ARN circular no codificante (ARNcirc) en las lesiones cardíacas relacionadas con la cardiotoxicidad inducida por quimioterapia y la infección por el SARS-CoV-2. Se descubrieron múltiples firmas moleculares de ARNcirc durante la remodelación de las células y tejidos cardíacos en modelos murinos y humanos. Los ARNcirc no codificantes son estables y se conservan entre especies, por lo que representan dianas farmacológicas ideales. El objetivo del proyecto es identificar ARNcirc fundamentales que intervienen en los procesos de remodelación mediante el uso de cribado con bibliotecas de CRISPR-Cas funcionales y la validación en un modelo de tejido miocárdico humano. Los candidatos seleccionados se probarán en modelos de cardiopatías derivadas de la cardiotoxicidad inducida por quimioterapia y por el SARS-CoV-2.
Objetivo
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.
Ámbito científico
- 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
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitución de acogida
30625 Hannover
Alemania