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

描述（由申请人提供）：主要研究者Changwon Kho博士目前是西奈山医学院心血管研究中心（CVRC）的分子和细胞心脏病学高级博士后研究员。该计划的最终目标是作为一个平台，在翻译心血管蛋白质组学的新兴领域开展独立的研究事业。K99/R 00研究策略的重点是深入表征参与心肌中Ca 2+处理的关键蛋白质的翻译后修饰的关系，及其作为支持生理功能障碍和心力衰竭的新分子途径的潜力。研究计划将通过围绕心血管病理生理学，信号网络和生物信息学的选定教学培训构建的职业发展计划进行补充;参加研讨会和会议，以及专业生存技能指导（例如实验室管理和资助申请写作）。K99和职业过渡模块将由西奈山CVRC主任Roger J. Hajjar医学博士监督。在与本申请的研究/职业目标相一致的领域中，有一组研究人员和合作者，他们具有心血管生理学，先进蛋白质组学，病毒载体构建和关键专业技能开发方面的专业知识。该研究源于PI进行的研究，其显示Ca 2+泵SERCA 2a与小泛素修饰剂1或SUMO 1的缀合导致小鼠心肌细胞中生物活性和心脏功能的深刻改变（Kho et al.，Nature，2011）。PI还发现SERCA 2a是后乙酰化的。PI提出了一种范式，通过这种范式，类小泛素化和乙酰化是调节SERCA 2a在衰竭心脏中的生物活性和功能的相反过程。K99阶段将专注于详细研究SERCA 2a翻译后乙酰化的生物学后果。具体而言，我们将表征心力衰竭小鼠模型中SERCA 2a相关的乙酰化（目的1），并将确定乙酰化在分子功能中的生物学作用（目的2）。在R 00阶段，PI将确定体内SERCA 2a的超乙酰化或低乙酰化的生理后果，并检查调节乙酰化的可能分子机制。此外，PI还设计了一项计划，以评价SERCA 2a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.