The sarcomere is the molecular motor of the heart. Contraction of the heart is finely tuned by regulatory proteins and in particular troponin I on the thin filament of the sarcomere. Cardiac troponin I function is modified by multiple post-translational modifications, including novel modifications we recently discovered. Modifications of troponin I are altered in heart failure and hypertrophic cardiomyopathy, a genetic disease of sarcomeric proteins. The investigator's laboratory has a long-term interest in post-translational changes in the myofilament proteins which contribute to systolic and diastolic dysfunction. The laboratory continues to focus on understanding the precise quantification of site specific post-translational modifications and the functional significance of specific modifications of troponin I This proposal will test hypotheses that post- translational modifications and disease allele specific protein expression in hypertrophic cardiomyopathy underlie some of the pathophysiologic manifestations of disease, and that novel phosphorylation sites on troponin I contribute to contractile pathophysiology in heart failure and hypertrophy.
The aims i nclude translational proteomics experiments to quantify mutant allele expression and hypertrophic cardiomyopathy associated phosphorylation alterations and linking these directly to function in human cardiomyocytes. Two novel TnI phosphorylations, discovered in the prior cycle, which are relevant to the heart failure phenotype, will also be functionally evaluated. These studies wil produce new therapeutic strategies which may target and compensate for these functional changes in hypertrophic as well as dilated cardiomyopathy and heart failure.
These studies are relevant to important clinical problems including heart failure and hypertrophic cardiomyopathy. Heart failure is a common disorder that affects an estimated 6 million people in the United States. Heart failure has estimated survival of only 50% within 5 years after diagnosis. Hypertrophic cardiomyopathy is a common genetic disease affecting 1/500 people and is the most common cause of sudden cardiac death in young athletes.
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