Objective Cardiovascular disease keeps the top spot in mortality statistics in Europe with 2 million deaths annually and although prevention and therapy have continuously been improved, the prevalence of heart failure continues to rise. While contractile (systolic) dysfunction is readily accessible to pharmacological treatment, there is a lack of therapeutic options for reduced ventricular filling (diastolic dysfunction). The diastolic properties of the heart are largely determined by the giant sarcomeric protein titin, which is alternatively spliced to adjust the elastic properties of the cardiomyocyte. We have recently identified a titin splice factor that plays a parallel role in cardiac disease and postnatal development. It targets a subset of genes that concertedly affect biomechanics, electrical activity, and signal transduction and suggests alternative splicing as a novel therapeutic target in heart disease. Here we will build on the titin splice factor to identify regulatory principles and cofactors that adjust cardiac isoform expression. In a complementary approach we will investigate titin mRNA binding proteins to provide a comprehensive analysis of factors governing titin’s differential splicing in cardiac development, health, and disease. Based on its distinctive role in ventricular filling we will evaluate titin splicing as a therapeutic target in diastolic heart failure and use a titin based reporter assay to identify small molecules to interfere with titin isoform expression. Finally, we will evaluate the effects of altered alternative splicing on diastolic dysfunction in vivo utilizing the splice deficient mutant and our available animal models for diastolic dysfunction.The overall scientific goal of the proposed work is to investigate the regulation of cardiac alternative splicing in development and disease and to evaluate if splice directed therapy can be used to improve diastolic function and specifically the elastic properties of the heart. Fields of science social sciencessociologydemographymortalitynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencescell biologymedical and health sciencesclinical medicinecardiologycardiovascular diseasesnatural sciencesbiological sciencesbiophysics Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS4 - ERC Starting Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2011-StG_20101109 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Coordinator MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC) Address Robert rossle strasse 10 13125 Berlin Germany See on map Region Berlin Berlin Berlin Activity type Research Organisations Principal investigator Michael Gotthardt (Prof.) Administrative Contact Ioannis Legouras (Dr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC) Germany EU contribution € 1 499 191,00 Address Robert rossle strasse 10 13125 Berlin See on map Region Berlin Berlin Berlin Activity type Research Organisations Principal investigator Michael Gotthardt (Prof.) Administrative Contact Ioannis Legouras (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Other funding No data
