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Functional Genomics of Familial Hypertrophic Cardiomyopathy


Familial hypertrophic cardiomyopathy (FHC) is a myocardial disease with the major feature of asymmetric septal hypertrophy (ASH). 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 s udden death in the young and is associated with a significant risk of heart failure. The major objective of the present project is the elucidation of the mechanisms by which cardiac myosin-binding protein C (cMyBP-C) mutations lead to FHC. Particularly, we will investigate two new concepts, the first one emerging from our recent data: (1) Impairment by truncated cMyBP-C mutants of the ubiquitin-proteasome system (UPS) as a pathogenic factor of FHC and (2) Specific mobilization and differentiation of recent ly identified Isl-1 positive cardioblasts as a cause of ASH. Other objectives concern the role of cMyBP-C in sarcomere structure and its phosphorylation in regulation of cardiac contraction. The recent development of two targeted cMyBP-C mice by L. Carrier will allow to resolve these issues. The heterozygous cMyBP-C null mice is the first model with ASH and will therefore enable us to identify the cause of this enigmatic alteration. L. Carrier and the Eschenhagen lab recently demonstrated that truncated cMy BP-Cs are substrates and inhibitors of the UPS. Impairment of the UPS in the pathogenesis of FHC is a novel concept in cardiology, which parallels the pathogenesis of some neurodegenerative disorders. The concept will be tested in cMyBP-Cmut/+ mice, which carry a mutation leading to a truncated cMyBP-C. The material and methods developed in the project are at the forefront of progress (targeted transgenesis, recombinant adenovirus, proteasome reporter mice, RNA interference, 3D-engineered heart tissue (inve nted and patented by T. Eschenhagen), echocardiography, Millar tip catheter, sarcomere length measurements, osmotic minipumps, confocal and electronic microscopy, transcriptome and proteome analysis).

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