Descripción del proyecto
Investigación de la interacción entre los complejos de sarcómeros y empalmosomas, y su relación con la insuficiencia cardíaca
La función cardíaca se adapta a la carga mecánica utilizando una red de factores de empalme que regula múltiples ARNm diana, la biomecánica cambiante, la actividad eléctrica, el metabolismo, la señalización y el crecimiento. El empalmosoma contiene un complejo de moléculas de ARN y proteínas de unión a ARN, cuya actividad se regula para adaptar la expresión de isoformas cardíacas y la mecánica de los sarcómeros. El proyecto MERAS, financiado por el Consejo Europeo de Investigación, explorará la mecanorregulación del empalme cardíaco en relación con las enfermedades cardíacas utilizando el análisis multiómico y la mecánica y secuenciación de isoformas de célula única. El objetivo del proyecto es investigar la interacción funcional de los complejos macromoleculares de empalmosomas y sarcómeros para evaluar la mecanotransducción como una posible diana terapéutica en la insuficiencia cardíaca.
Objetivo
To adapt cardiac function in response to mechanical load, a network of splice factors concertedly regulates multiple target mRNAs that affect biomechanics, electrical activity, metabolism, signaling, and growth. It includes the splice regulator RBM20, with mutations causing severe cardiomyopathy, as well as its substrate titin, whose >350 exons are differentially joined to adjust the elastic properties of the sarcomere and thus ventricular filling. In the spliceosome, diverse RNAs and RNA binding proteins interact in macromolecular complexes, but how their activity is regulated to adapt cardiac isoform expression and sarcomere mechanics has remained elusive.
We have adapted localization proteomics to study macromolecular complexes in vivo at physiological expression levels, which has previously not been possible. Our titin-BioID knock-in mice have provided the first census of the sarcomeric proteome and uncovered a previously unknown connection between sarcomeric mechanotransduction and mRNA processing in the nucleus. This unexpected link is the basis of our hypothesis that altered strain of the titin filament is communicated to the nucleus where the spliceosome adapts titin isoform expression to adjust sarcomere elasticity. This proposed regulatory feedback loop would elegantly resolve the question of how sarcomeres adapt to mechanical load.
Here, we will explore how the mechanoregulation of cardiac splicing contributes to heart disease in a functional multi-omics approach and develop technologies that combine single cell isoform sequencing and mechanics to examine how heterogeneity of the mechanical microenvironment determines isoform expression in the individual cardiomyocyte.
The overall scientific goal of the proposed work is to investigate the functional interaction of two macromolecular machines – the sarcomere and the spliceosome – and to evaluate mechanotransduction as a potential therapeutic target in heart failure with increased ventricular stiffness.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
13125 Berlin
Alemania