Familial hypertrophic cardiomyopathy (FHC) is a disease of the sarcomere where the resulting hypertrophy is associated with pump failure of arrythymias. The sarcomeric alterations involve point mutations in the myosin molecule or in other proteins (thin filament and C protein). In this study we use genetically altered (heterozygous and homozygous) mice that mimic some of the key point mutations found in FHC (myosin: R403Q, V606M, D778G; G741R, R719Q, G584R; alpha-tropomyosin: D175N; and troponin- T:I79N). Permeabilized papillary muscle strips (skinned fibers) will be studied mechanistically to provide a detailed functional characterization of mutant contractile proteins within the spatial constraints of the structured fibers. The mechanical analysis will in turn be compared with correlative in vivo ventricular function studies and single molecule mechanics. From our studies we expect to be able to characterize the mechanical alterations found in the disease in terms of power output, force absorbing and force producing elements, velocity, cross-bridge kinetic parameters and calcium sensitivity. From this analysis we anticipate being able to define the key elements that lead to the pump failure and thus the potential targets for therapeutic intervention. In addition, the point mutations in specific regions of the myosin molecule as well as in the thin filament proteins (tropomyosin and troponin) will allow us to develop new insights into the contribution of small structural changes (point mutations) to the functional alterations.
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