Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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The contractile elements or sarcomeres are comprised of multiple thin and thick filament proteins that are important determinants of the structure and function of the heart. Contractile proteins are one of the primary means of regulating contractile function, because they possess or regulate the enzymatic machinery that hydrolyzes ATP to provide the energy for contraction. This enzymatic activity- myofibrillar ATPase-is activated by actin binding to myosin. The actual enzyme myosin ATPase, resides in the myosin heavy chain (MyHC) head region. The genes and functional expression of several key contractile proteins that possess or regulate ATPase activity are altered in the failing human heart. Major abnormalities have been detected by our group and others in the mRNA and/or protein expression of MyHC, myosin light chains, and troponin T isoforms. Additionally, the potential exists for as yet undetected abnormalities in the gene/protein expression of other sarcomere components whose altered expression can change function or produce a cardiomyopathy phenotype in transgenic animals. Despite the obvious potential for altered contractile protein expression to contribute to the development and progression of myocardial failure and cardiomyopathies, there has not been a comprehensive examination of this system in the failing vs. nonfailing human heart. This application proposes such an investigation, to be conducted exclusively in human ventricular myocardium. The proposal will 1) further and comprehensively characterize sarcomeric gene and protein expression in the failing and nonfailing human heart, 2) determine if normalization of the alpha-/beta-MyHC ratio improves intrinsic systolic function in the human heart, and 3) investigate a potential molecular mechanism (down-regulation of stimulatory thyroid hormone receptors) for the coordinate dysregulation of MyHC isoforms in the failing human heart. This investigation will be conducted in explanted hearts, isolated tissue preparations of functioning myocardium, and in the intact heart. The data generated in this proposal should determine if altered expression of contractile proteins is a molecular explanation for systolic dysfunction in the failing human heart, and if this system can be targeted therapeutically.
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