Thursday, November 21, 2024
11/21/2024
Cardiomyopathies are a significant cause of death and morbidity with limited treatment options. A substantial fraction (30-60%) of these cardiomyopathies has been identified as “diseases of the sarcomere” having their origin in point mutations in sarcomeric proteins leading to dysregulation of acto- myosin interactions with consequent functional deficits. Current therapies are mostly not disease specific and focus on symptoms rather than on mitigating the root causes in sarcomere dysregulation. Muscle contractility is governed by both the classic and extensively studied Ca2+-mediated thin filament- based regulatory mechanism and newly discovered, but very poorly understood, thick filament based regulatory mechanisms. In this proposal, our over-arching hypothesis is that thick filament regulatory mechanisms are critical modulators of muscle function. Improved understanding of these mechanisms will identify novel drug targets, and the desired characteristics of therapeutic compounds, that are necessary to mitigate the structural and functional defects underlying myocardial pathophysiology. We have demonstrated that porcine myocardium, the closest model system for human hearts, is an excellent experimental system for our proposed structural and functional driven studies, with the expected findings readily extrapolatable to humans. We propose to investigate the structural, biochemical, and mechanical aspects of thick filament regulation mechanisms from porcine myocardium. Specifically, in Aim 1, we will decouple classical Ca2+ dependent thin filament-based regulation from the newly discovered Ca2+ dependent thick filament-based regulation mechanism by exchanging the native troponin complex with exogenous D65A troponin complex that abolishes Ca2+ binding capability to reveal the details of molecular mechanism and the physiological significance of this mechanism. In Aim 2, we will evaluate thick filament backbone stiffness from both actively contracted and passively stretched porcine myocardium to investigate the underlying mechanisms of myofilament length dependent activation. In Aim 3, we will interrogate the structural, biochemical and mechanical consequences of porcine myocardium in response to PKA treatment. Finally, in Aim 4, we will extend the new findings regarding thick filament regulatory pathways in healthy porcine myocardium to the pathological basis of thick filament dysregulation in hypertrophic, dilated and restrictive cardiomyopathies (HCM, DCM and RCM respectively) model porcine hearts. Results are expected to have immediate translational relevance by identifying potential therapeutic targets for sarcomere-based cardiomyopathies.
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