Description du projet
ARN non codants longs et maladies cardiovasculaires liées au vieillissement
L’augmentation de l’espérance de vie est corrélée à la prévalence des maladies cardiovasculaires dues à l’âge dans l’Union européenne. L’insuffisance cardiaque à fraction d’éjection préservée (ICFEP), qui fait partie des maladies cardiovasculaires liées au vieillissement, est une forme complexe impliquant plusieurs types de cellules et faisant intervenir plusieurs mécanismes, ce qui aboutit à une relaxation altérée des cardiomyocytes. Le projet NICCA, financé par l’UE, a pour objectif d’étudier les mécanismes moléculaires impliqués dans la communication intercellulaire et le vieillissement qui entraîne une ICFEP. Les ARN non codants longs (ARNlnc) apparaissent comme des régulateurs essentiels au niveau des fonctions cellulaires et pourraient contribuer à un dysfonctionnement cardiaque lié au vieillissement, comme l’ICFEP. Comprendre le rôle des ARNlnc dans le vieillissement cardiaque et dans l’ICFEP fournira de nouvelles cibles thérapeutiques qui permettront d’atténuer le dysfonctionnement cardiaque lié au vieillissement.
Objectif
Life expectancy in the European Union is rising and the prevalence of age-induced cardiovascular disease increases concomitantly. The main clinical presentation of age-induced cardiovascular disease is heart failure with preserved ejection fraction (HFpEF). HFpEF is a complex disease involving different cell types and mechanisms that contribute to impaired relaxation of cardiomyocytes. Currently there is no appropriate treatment for HFpEF. This proposal aims to better understand the molecular mechanisms behind intercellular communication and ageing that lead to HFpEF.
Long non-coding RNAs (lncRNAs) are emerging as novel key regulators of cellular functions and we hypothesize that lncRNAs contribute to ageing-induced cardiac dysfunction, including HFpEF. Preliminary experiments show that several long non-coding RNAs (lncRNAs) are differentially regulated during cardiac ageing, including the cardiomyocyte-enriched lncRNA Sarrah that is essential for cardiomyocyte survival. We propose to extensively characterize the role of Sarrah in HFpEF and to identify other lncRNAs that are involved in cardiac ageing. Importantly, we will focus those lncRNAs that are also affected in a cohort of human HFpEF patients. Furthermore, since disturbed intercellular communication is a hallmark of both ageing and HFpEF, we will identify lncRNAs that regulate endothelial cell-cardiomyocyte crosstalk. We will use state-of-the-art in vitro and in vivo models to assess cardiac ageing and function upon gain-of-function and loss-of-function of lncRNAs in a cell-type specific manner.
Understanding the role that Sarrah and other lncRNAs play in cardiac ageing and HFpEF will highlight novel potential therapeutic targets to attenuate age-induced cardiac dysfunction and will increase our knowledge of the underlying mechanisms controlling intercellular communication and cardiac function.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
1081 HV Amsterdam
Pays-Bas