We propose to study heart failure in beta cardiac MHC gene missense mutations. Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominantly inherited disorder of heart muscle. Individuals with FHC- causing mutations develop cardiac hypertrophy and myocyte disarray and are at significantly increased risk of heart failure and/or sudden death. About 40% of individuals with FHC have missense mutations in their beta cardiac MHC gene. A broad spectrum of clinical symptoms is found among individuals with the same beta cardiac MHC mutation. However, some beta cardiac MHC mutations are associated with high morbidity and mortality whereas others appear to have a more modest effect on life expectancy. Under the auspices of this grant we will use homologous recombination to produce mouse models of FHC. These murine models will enable us to further define the biologic consequences of specific mutations on cardiac structure and function. We will assess the role of other factors (both genetic and environmental) that modulate the hypertrophic phenotype. These animal models will also be invaluable for assessing energetics of the pre- symptomatic and symptomatic hypertrophic myocardium as well as providing tissue reagents for analyses of signal transduction pathways that may be perturbed in heart failure. Analyses of these mice will be greatly facilitated by our association with the SCOR. In particular, the progress and experience obtained in Projects 1, 3 and 4 of the SCOR in characterizing murine cardiac function will be necessary for our studies of mice bearing myosin mutations. Specifically we propose to: 1) Create mice bearing FHC-causing mutations by homologous recombination. 2) Define the effects of myosin mutations on cardiac development and structure. 3) Define and compare the phenotypes associated with each mutation, specifically to assess energetics and signal transduction pathways of genetically altered myocardium. 4) Assess the role of genetic background on the phenotypes associated with each mutation; to vary environmental factors (i.e. hormones, diet and exercise) and assess the effects on the pathophysiologic process. The creation of a genetic murine model of FHC will eventually allow us to take rational approaches to the development of pharmacologic therapies and behavioral modification that should benefit individuals with FHC. Ultimately, these studies will improve therapy of hypertrophy from many etiologies and may prevent heart failure.
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