The Principal Investigator, Dr. Changwon Kho, is currently an advanced postdoctoral fellow in molecular and cellular cardiology in the Cardiovascular Research Center (CVRC) of the Mount Sinai School of Medicine. This proposed program has as its ultimate goal to serve as platform to launch an independent investigative career in the emerging field of translational cardiovascular proteomics. The K99/R00 research strategy centers on undertaking an in-depth characterization of the relationship of postranslational modifications of key proteins involved in Ca2+-handling in the myocardium and their potential as new molecular pathways underpinning physiological dysfunction and heart failure. The research plan will be complemented by a career development program structured around selected didactic training in cardiovascular pathophysiology, signaling networks and bioinformatics;attendance at seminars and conferences, as well as guidance in professional survival skills (e.g. laboratory management and grant application writing). The K99 and career transition modules will be under the oversight of Roger J. Hajjar, MD, Director of the Mount Sinai CVRC. In areas aligning with the research/career objectives of this application are a group of investigators and collaborators with expertise in cardiovascular physiology, advanced proteomics, viral vector construction and development of crucial professional skills. The research stems from studies conducted by the PI showing that conjugation of the Ca2+ pump SERCA2a with the small ubiquitin modifier 1 or SUMO1 results in profound alterations in biological activity in cardiomyocytes and in cardiac function in mice (Kho et al., Nature, 2011). The PI also discovered that SERCA2a was posttranslationally acetylated. The PI proposes a paradigm by which sumoylation and acetylation are opposing processes modulating SERCA2a's biological activity and functioning in the failing heart. The K99 phase will focus on detailed study of the biological consequences posttranslational acetylation of SERCA2a. Specifically we will characterize SERCA2a-associated acetylation in mouse models of heart failure (Aim 1) and will determine the biological role of acetylation in molecular function (Aim 2) In the R00 phase the PI will determine the physiological consequences of hyper- or hypo-acetylation of SERCA2a in vivo and examine possible molecular mechanisms modulating acetylation. In addition, the PI has designed a plan to evaluate the use of small molecule inhibitors of SERCA2a acetylation as an alternative approach towards creating novel classes of cardiotherapeutics.
One of hallmarks of heart failure is an abnormal function of the sarcoplasmic reticulum Ca2+-ATPase pump (SERCA2a), which is a critical protein in cardiac cel relaxation. We have found that acetylation affects the function of SERCA2a and that this post-translational modification, occurring on lysine residues, may determine the overall performance of the ventricle in the setting of heart failure. The outcome of this proposal will demonstrate that SERCA2a activity might be manipulated by post- translational modification.
|Hajjar, Roger J; Lyon, Alexander R (2014) Gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. Circulation 129:2633-5|