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Mechanoregulation of alternative splicing - a multi-omics and single cell approa...
Mechanoregulation of alternative splicing - a multi-omics and single cell approach to improved cardiac function
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 sp...
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.
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Duración del proyecto: 64 meses
Fecha Inicio: 2022-08-30
Fecha Fin: 2027-12-31
Fecha Fin: 2027-12-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-08-30
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2021-ADG:
ERC ADVANCED GRANTS
Cerrada
hace 3 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN...
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Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5