Mutations in cardiac thin filament regulatory protein, Troponin T, have recently been linked to Familial Hypertrophic Cardiomyopathy, a cause of sudden death in young people. The severity of the disorder is not related to the degree of hypertrophy and is more likely to be due to alterations in cardiovascular physiology at the cellular level. Prior work in the lab has established that varied phenotypes at the whole-organ level are determined by distinct mutation-specific alterations in the thin filament. Specifically, altered flexibility in the N- terminal portion of TnT affects thin filament function and alters downstream myocellular signaling pathways. Changes in Ca2+ kinetics also contribute to pathogenesis. It can be hypothesized that cTnT mutations undergo mechanisms in which thin-filament protein interactions may be disrupted due to changes in flexibility resulting in altered physiologic signaling, which drives distinct phenotypes. The changes in flexibility of cTnT and its effects on thin filament function will be investigated. Changes in mechanics and Ca2+ homeostasis in cTnT mutation (Arg92Trp) will be characterized, which are a result of affected myocellular signaling pathways (beta-adrenergic and calmodulin kinase II activity) and temporal patterns also under investigation. ? ? ?
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