The long-term goal of the research program outlined in this application is to establish the mechanisms that link structural mutations in thin filament proteins to the development of Familial Hypertrophic Cardiomyopathy (FHC). During the original granting period we established that independent disease mutations at Residue 92 of cTnT (R92Q, R92W and R92L) result in discrete, mutation-specific alterations in cTnT structure and protein dynamics, energetics and contractile reserve, -adrenergic responsiveness and myocellular Ca2+ homeostasis. Moreover, many of these downstream cellular processes exhibit mutation-specific temporal changes that determine the progression of the resultant cardiomyopathy. Independent amino acid substitutions at a single residue of cTnT are thus sufficient to cause disparate physiologic phenotypes, and these phenotypes are the eventual result of specific changes in biophysical properties of the cTnT molecule. We have now developed the molecular, computational, cellular and whole-heart based tools to directly address this hypothesis and they define an integrative approach to establishing and eventually modifying the mechanistic link between mutations in cTnT and the malignant clinical course of FHC. These proposed studies are designed to both further our understanding of the pathogenesis of FHC and to provide new insights into the fundamental physiology and biophysics of the thin filament. In order to complete this research program we will implement the following three Specific Aims:
Aim 1 : To identify, evaluate and functionally }rank} the effects of known TNT1 mutations on the flexibility and structure of the 70-170 peptide around the critical }hinge} residue 104.
Aim 2 : To determine whether reducing the cost of contraction rescues the mutation-specific energetic-mechanical phenotypes of R92Q, R92L and R92W cTnT mutant hearts.
Aim 3 : To determine the mechanism(s) underlying the observed alterations in -adrenergic responsiveness in the R92 cTnT mutant hearts at the myofilament level. The completion of the studies will extend our understanding of how mutations in cTnT are mechanistically linked to their complex, malignant phenotype at the level of protein dynamics, cost of contraction, and energy reserve and the crucial myofilament response to -adrenergic stimulation. Moreover, we believe that these studies will both establish a new computational-functional paradigm for the study of thin filament cardiomyopathies and further expand our understanding of myofilament activation at the level of the cardiac sarcomere. Familial Hypertrophic Cardiomyopathy is one of the most common causes of sudden cardiac death in young people and the form of the disease caused by mutations in the thin filament protein cardiac Troponin T comprises a particularly malignant subset. The goal of this research project is to develop a integrated approach that utilizes computational modeling, development of rigorous genotype-molecular phenotype correlations and eventual whole-heart studies in animal models. The end result will be a better understanding of how these individual mutations in sarcomere proteins lead to severe cardiac disease and eventually lead to genotype-specific therapeutics for this currently untreatable disorder.
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|Tardiff, Jil C (2016) The Role of Calcium/Calmodulin-Dependent Protein Kinase II Activation in Hypertrophic Cardiomyopathy. Circulation 134:1749-1751|
|Sequeira, Vasco; Najafi, Aref; McConnell, Mark et al. (2015) Synergistic role of ADP and Ca(2+) in diastolic myocardial stiffness. J Physiol 593:3899-916|
|Tardiff, Jil C; Carrier, Lucie; Bers, Donald M et al. (2015) Targets for therapy in sarcomeric cardiomyopathies. Cardiovasc Res 105:457-70|
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