Cellular Mechanisms in the Pathogenesis of FHC

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DESCRIPTION (provided by applicant): While the genetic basis for many of the familial cardiomyopathies has been well established, the molecular mechanisms that underlie the pathophysiology of these disorders is only beginning to be delineated. Familial Hypertrophic Cardiomyopathy (FHC) is a primary myocardial disorder characterized by a striking degree of both genetic and clinical heterogeneity. To date, all of the mutations linked to FHC encode sarcomeric proteins. Mutations in the cardiac Troponin T (cTnT) gene result in a particularly poor clinical outcome. Patients with cTnT mutations exhibit a high frequency of early sudden cardiac death, often in the absence of significant left ventricular hypertrophy. The cardiac troponin complex plays a central role in modulating the response of the contractile apparatus to changes in intramyocellular conditions. One possibility is that cTnT mutations cause alterations in contractile function and lead to distinct myocellular responses which may result in maladaptive changes in cardiovascular physiology. In order to address this question we have recently developed two independent transgenic mouse models which express cTnT-related FHC alleles in the adult heart. One mutation results in a substitution of a Gin residue for Arg at Codon 92 (R92Q) while the other is a splice-site donor mutation which leads to a truncation of the 3' end of the cTnT protein (Trunc). These two mouse models recapitulate many of the characteristics of human FHC and also demonstrate that mutations in different cTnT functional domains result in distinct changes in cardiovascular function at the cellular, pathologic and whole-heart levels. Our central hypothesis is that these allele-specific differences are caused by inappropriate activation of specific intracellular signaling pathways and we will use these two animal models to fully test this possibility. A better understanding of these processes may well lead to specific therapeutic interventions which could alter the malignant natural history of this disorder.