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Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 13286686

Familial hypertrophic cardiomyopathy (FHC) is a myocardial disease with the major feature of asymmetric septal hypertrophy. It is one of the most common monogenic diseases with a disease prevalence of 1:500 in young adults. It is the major cause of sudden death in the young and is associated with a significant risk of heart failure. The objective of the present project is to investigate the role of the ubiquitin-proteasome system (UPS) and its various components in the pathophysiology of FHC. The project bases on our recent data demonstrating in cardiac myocytes that truncated cMyBP-Cs are not only substrates of the UPS but also inhibitors. Impairment of the UPS could lead to cardiac hypertrophy by a general decrease in protein degradation or by reduced degradation of growth promoting signaling elements. The involvement of such mechanism in FHC is a novel concept in cardiology, which parallels the pathogenesis of some neurodegenerative disorders. The concept will be tested in vivo in different mutant cMyBP-C mice developed by the team by additional or targeted transgenesis. In addition, several experiments will be performed in neonatal rat cardiac myocytes to decipher the role of recently identified ubiquitin ligases in the regulation of cMyBP-C expression and cardiac hypertrophy.