Descripción del proyecto
ARN no codificantes de cadena larga y enfermedades cardiovasculares asociadas a la edad
En la Unión Europea, la mayor esperanza de vida está correlacionada con la prevalencia de enfermedades cardiovasculares. Una de las enfermedades cardiovasculares asociadas a la edad es la insuficiencia cardíaca diastólica, una patología compleja que implica a distintos tipos celulares y mecanismos que llevan a una relajación alterada de los cardiomiocitos. El proyecto financiado con fondos europeos NICCA pretende estudiar los mecanismos moleculares tras la comunicación intercelular y el envejecimiento que conducen a la insuficiencia cardíaca diastólica. Se considera que los ARN no codificantes de cadena larga (ARNncl) son reguladores fundamentales de las funciones celulares y podrían contribuir a la disfunción cardíaca inducida por la edad, lo que incluye la insuficiencia cardíaca diastólica. Comprender el papel de los ARNncl en el envejecimiento cardíaco y la insuficiencia cardíaca diastólica proporcionará nuevas dianas terapéuticas para atenuar la disfunción cardíaca inducida por la edad.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
1081 HV Amsterdam
Países Bajos