The overall objective of this research project is to evaluate strategies for treating cardiac disease with viral gene transfer. The initial aspect of the project is to further delineate the functional consequences of mutations in sarcomeric proteins that have been linked to hypertrophic cardiomyopathy (HCM). There are several known genes in which mutations lead to HCM: 1) cardiac myosin heavy chain, 2) cardiac essential light chain of myosin, 3) cardiac regulatory light chain of myosin, 4) cardiac troponin T, 5) cardiac troponin I, 6) alpha-tropomyosin, and 7) cardiac myosin binding protein C. We will focus a novel myocyte culture system to evaluate the structure and functional ramifications of the mutations. The second aspect of the project will utilize two viral vector systems that hold potential for cardiac gene therapy: fully deleted adenovirus and recombinant adeno-associated virus (AAV) to attempt gene therapy in mouse models of hypertrophic cardiomyopathy (HCM). Using these transgenic mouse models of the disease, we will attempt replacement of mutant cardiac troponin T and myosin light chains via over-expression using recombinant AAV adenovirus. For mice with myosin heavy chain mutations, as well as in normal mice, we will evaluate strategies to alter calcium handling within the cardiocytes, also using viral gene transfer.
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