The long-range goal of this proposal is to define the mechanisms by which mutations in cardiac myosin binding protein C (MyBPC) cause hypertrophic (HCM) and dilated cardiomyopathy (DCM), a disease that affects 0.2% of the population worldwide, and is the leading cause of sudden death in young adults. Mutations in MyBPC are among the most common causes of inherited cardiomyopathy accounting for more than 40% of all known cases, and are associated with heart failure and sudden cardiac arrest. Because MyBPC is a critical modulator of actomyosin interactions, the initial functional deficit caused by mutations in MyBPC is expected to manifest as a defect in the regulation of cardiac muscle contraction at the myofilament level. However, the precise molecular mechanisms by which mutations in MyBPC alter contractile function and cause disease are not understood, and it has yet to be established if MyBPC expressing mutations can incorporate into the sarcomere to directly alter contractile function. A lack of fundamental insights into how MyBPC mutations cause HCM and DCM severely limits our ability to devise effective therapies to overcome the disease and its functional consequences. The proposed experiments will elucidate the functional effects of mutations in MyBPC known to cause a range of disease severity in children and adults, and will test the hypothesis that missense mutations in MyBPC incorporate into the sarcomere to directly alter contractile function in three principal aims designed to: 1) Establish the functional effects of MyBPC mutations on the Ca2+-dependencies of steady-state force and dynamic cross-bridge function in cardiac fibers reconstituted with MyBPC expressing HCM and DCM causing mutations, 2) Define the effects of MyBPC mutations on ATPase activity, thin filament regulation of force generation, and cross-bridge kinetics, using steady-state and transient kinetic analysis of fluorescently labeled proteins, and 3) Determine the in vivo functional consequences of missense mutations in MyBPC by assessing ventricular structure and function using pressure-volume catheterization and high resolution cardiac magnetic resonance imaging in animals subjected to acute gene transfer of mutant MyBPC. It is expected that results from these integrative studies will provide novel insights of the underlying mechanisms by which mutations in MyBPC cause cardiac dysfunction and will aid in the development of novel therapeutic strategies for treatment MyBPC related HCM and DCM.
Familial hypertrophic cardiomyopathy (FHC) is highly prevalent inherited cardiac disease and is the most common cause of sudden death in adolescents and young adults. Mutations in cardiac myosin binding protein C (MyBPC) are a leading cause of H+FHC in humans, however the mechanisms by which these mutations cause disease are not understood. This proposal will address this important deficiency in our understanding of the mechanisms of MyBPC related FHC, specifically, how they affect cardiac muscle function. Results from these studies will contribute to the development of novel therapies to improve cardiac function in MyBPC related FHC.
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|Gresham, Kenneth S; Mamidi, Ranganath; Stelzer, Julian E (2014) The contribution of cardiac myosin binding protein-c Ser282 phosphorylation to the rate of force generation and in vivo cardiac contractility. J Physiol 592:3747-65|
|Cheng, Y; Wan, X; McElfresh, T A et al. (2013) Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere. Am J Physiol Heart Circ Physiol 305:H52-65|