SP 2

Integration of mechanotransduction and pathogenesis of dilated cardiomyopathy and heart failure

Cardiomyopathies account for a significant number of patients suffering from heart failure (HF). The underlying molecular processes involve several signaling events including the sensing and transduction of biomechanical stress (mechanotransduction). The aim of this project is to systematically explore the mechanical stress-activated pathways contributing to the development of dilated cardiomyopathy utilizing a combined experimental and bioinformatics approach.

Z-disc-associated cardiac signaling pathways involved in mechanotransduction (figure modified from Frank & Frey, J Biol Chem, 2011)

Our existing expression profiling data sets of comprehensive in vitro (heart muscle cell stretch models) and in vivo data (mouse models of dilated cardiomyopathy) will be used:

(1) to integrate these data on mRNA and microRNA (miR) expression profiles from closely related models with the goal to identify underlying central mechanisms involving signaling molecules and miRs.

(2) to analyze these genes/proteins and miRs in vitro and

(3) in vivo (one knockout mouse model) in the context of (biomechanical) stress

(4) to translate the results into an adeno-associated virus (AAV)-based gene-therapy approach