Post-translational mechanisms of cardiac adaptation during unloading

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PROJECT SUMMARY Cardiovascular diseases are responsible for more deaths each year than cancer, which is why it is important to study how to keep hearts healthy. Hearts undergo physiological remodeling; this is a structural and functional adjustment that matches contractile capacity to hemodynamic demand. In cardiomyocytes, hormonal and mechanosensitive signaling pathways maintain the balance between normal cell size, hypertrophy, or atrophy. Pathologies develop when the adequate adaptation to a stimulus is mismatched. My long-term goal is to establish an independent research program on understanding how mechanical load affects myocardial structure and function and what are the contributing molecular mechanisms. My recent publication in the Journal of General Physiology shows that changing mechanical stimulus of cardiac myocytes affects the dynamics and post-translational modification of the Z-disc actin-capping protein CapZ. I wish to extend this in a new direction working as an independent investigator. Accordingly, my central hypothesis is that mechanical load of cardiomyocytes regulates protein homeostasis in sarcomeres through the balance between acetylation and ubiquitination of lysine residues. Histone deacetylase 3 (HDAC3) is one known acetylation enzyme of sarcomeric proteins. I focus on the Z-disc proteins CapZ and α-actinin because they both maintain sarcomere integrity and because acetylation sites have been previously found in both proteins. My preliminary data shows that unloading changes the relative abundance of CapZ and α-actinin ubiquitination and acetylation. The goal of the K99 mentored phase is (1) to determine post-translational modifications arising from chemical or mechanical unloading of isolated cardiomyocytes with focus on acetylation and K48-oligo-ubiquitination. The goals of the R00 independent phase are (2) to characterize how HDAC3 activity in cardiomyocytes regulates α-actinin and CapZ deacetylation with varying mechanical load and (3) to determine the changes in post- translational modification of sarcomeric proteins by HDAC3 during left-ventricular unloading in whole hearts. The innovation of this project lies in the combination of cardiomyocyte mechanobiology with post-translational molecular biochemistry to understand how cardiac cells maintain sarcomeric protein balance through the ubiquitin-acetylation pathway in response to mechanical stimuli. The outcomes of this project will expand our knowledge about the signaling pathways responsible for modulating protein homeostasis in cardiomyocytes that may develop new research lines for regulation in hypertrophic cardiomyopathies and sarcopenia. The career development activities in this proposal, in addition to the exceptional mentoring team and research environment at the University of Illinois at Chicago, will support my successful transition to a career as an independent investigator.