Thursday, November 21, 2024
11/21/2024
Over the past several decades, and accelerating in recent years, the sarcomere has been appreciated as both the hotspot for cardiomyopathy-causing variants and as a promising drug target. These variants can alter the structure and regulation of the sarcomere, leading to altered function. The field has made significant progress in understanding these effects using various models and while each of these have strengths, they all have caveats that limit their utility in understanding the in vivo impact of cardiomyopathy-inducing variants. The porcine heart, the most accurate animal model of human hearts, has similar isoform composition, structure, heart rate, and response to physiological stimuli, allowing studies on live muscle that are not feasible with biobanked human samples. Our research team is uniquely suited for the sophisticated experiments necessary to perform these studies. To interrogate the structural impact of these variants, we will use synchrotron X-ray diffraction, the only technique capable of obtaining molecular level sarcomere structural data from live cardiac muscle. Sarcomere function will be assessed both at Argonne and at nearby Loyola University Chicago on custom biophysical setups. Lastly, sarcomere structure and function are regulated by protein post-translational modifications (PTMs) and isoform switching, which will be assessed using our top-of-the-line mass spectrometry instrumentation. We will investigate the structural basis of myofilament functional dysregulation in healthy, hypertrophic (HCM: MYH7R403Q, MYBPC330X), dilated (DCM: TTN16648X, RBM20R636S) cardiomyopathy transgenic pigs across the following three aims. These studies will reveal the underlying structural basis for cardiomyopathies resulting from sarcomere protein variants, revealing translational mechanistic understanding necessary to treat these diseases. In Aim 1 we will determine the impact of HCM and DCM mutations on normal sarcomere structure. We will collect X-ray diffraction patterns and functional data from live porcine cardiac muscle to investigate the structural basis of protein variants leading to HCM and DCM. In Aim 2 we will determine the impact of physiological inotropic interventions in HCM and DCM. A major pathological mechanism of these disease-causing variants is that they modify the sarcomere’s ability to respond appropriately to normal physiological conditions. Here we will assess the response to conditions which typically elicit an ionotropic response. In Aim 3 we will determine how HCM and DCM mutations affect sarcomere function regulation by post-translational modifications.
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