The Role of Post-translational Acetylation in SERCA2a-related Cardiac Dysfunction

描述(申请人提供)：首席研究员高昌元博士目前是西奈山医学院心血管研究中心分子和细胞心脏病学高级博士后研究员。这一拟议计划的最终目标是作为平台，在新兴的转译心血管蛋白质组学领域启动独立的研究生涯。K99/R00的研究策略集中于深入描述参与心肌钙处理的关键蛋白的翻译后修饰与它们作为新的支持生理功能障碍和心力衰竭的分子通路的潜力之间的关系。该研究计划将得到围绕心血管病理生理学、信号网络和生物信息学方面的选定教学培训、出席研讨会和会议以及专业生存技能指导(例如，实验室管理和拨款申请撰写)的职业发展计划的补充。K99和职业过渡模块将由西奈山CVRC主任罗杰·J·哈贾尔医学博士监督。与该应用程序的研究/职业目标保持一致的领域是一群研究人员和合作者，他们具有心血管生理学、高级蛋白质组学、病毒载体构建和关键专业技能开发方面的专业知识。这项研究源于PI进行的研究，该研究表明，钙泵SERCA2a与小泛素修饰物1或SUMO1的结合导致心肌细胞的生物活性和小鼠心脏功能的深刻变化(Kho等人，自然，2011年)。PI还发现SERCA2a是翻译后乙酰化的。PI提出了一个范例，通过这个范例，SUMO化和乙酰化是调节SERCA2a的生物活性和在衰竭心脏中发挥作用的相反过程。K99阶段将集中于详细研究SERCA2a翻译后乙酰化后的生物学后果。具体地说，我们将在心力衰竭的小鼠模型中表征SERCA2a相关的乙酰化(目标1)，并将确定乙酰化在分子功能中的生物学作用(目标2)。在R00阶段，PI将确定体内SERCA2a的高乙酰化或低乙酰化的生理后果，并检查可能调节乙酰化的分子机制。此外，PI还设计了一项计划，以评估SERCA2a乙酰化小分子抑制剂作为创建新型心脏治疗药物的替代方法的使用。

DESCRIPTION (provided by applicant): 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.