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Mechanoregulation of alternative splicing - a multi-omics and single cell approach to improved cardiac function

Projektbeschreibung

Untersuchung der Interaktion zwischen Sarkomer und Spleißosomenkomplexen und der Verbindung zur Herzinsuffizienz

Die Herzfunktion passt sich der mechanischen Belastung mithilfe eines Netzwerks aus Spleißfaktoren an, das mehrere Ziel-mRNS reguliert und damit die Biomechanik, die elektrische Aktivität, den Stoffwechsel, die Signalübertragung und das Wachstum verändert. Das Spleißosom enthält einen Komplex aus RNS und RNS-bindenden Proteinen, deren Aktivität reguliert wird, um die Expression von Herz-Isoformen und die Sarkomermechanik anzupassen. Im Rahmen des vom Europäischen Forschungsrat finanzierten Projekts MERAS wird die Mechanoregulation des kardialen Spleißens im Zusammenhang mit Herzerkrankungen mittels Multiomik-Analysen und Einzelzell-Isoformen-Sequenzierung und Mechanik untersucht. Projektziel ist die Erforschung der funktionellen Interaktion des Sarkomers und der makromolekularen Komplexe des Spleißosoms, um die Mechanotransduktion als potenzielles therapeutisches Ziel bei Herzinsuffizienz zu bewerten.

Ziel

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.

Programm/Programme

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Koordinator

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
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€ 2 499 999,00
Adresse
Robert rossle strasse 10
13125 Berlin
Deutschland

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Berlin Berlin Berlin
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