Pathophysiological Regulation of Metabolism and Energy Use during Heart Failure

项目摘要/摘要 这项建议的目标是：1)培养格雷戈里·奥伯特博士成为一名成功的 心血管疾病领域的内科科学家研究员，专注于心脏代谢，以及2) 更好地概述磺酰脲受体2(SUR2)在控制心肌细胞代谢中的作用 生理应激源，更具体地说，在心力衰竭的发展过程中。此应用程序已被 旨在帮助Aubert博士成功地过渡到研究生水平的独立调查员 洛约拉·斯特里奇医学院和西北临床医学院的初级教员课程 翻译科学研究所和跨学科生物科学计划2)发展 精通新的科学方法，如人类诱导多能干细胞(HiPSC) 心肌细胞和基因编辑，3)提高科学交流和转化医学的技能 通过结构化的指导。目前许多治疗心力衰竭的方法都是针对心脏功能紊乱。 神经激素轴，不直接以心肌细胞为靶点。越来越多的证据表明， 心肌细胞能量代谢和底物利用是心力衰竭发生的关键因素。 然而，导致这种代谢转变的确切机制还没有被很好地描绘出来。人类基因 研究发现，在扩张型糖尿病的发生过程中，编码SUR2的ABCC9基因发生了突变 心肌病和室性心律失常。ABCC9/SUR2基因全局缺失的小鼠在 新生儿窗口期未能正常过渡到氧化代谢。鉴于SUR2的作用及其 伙伴蛋白来调节心脏能量学，我们相信这种蛋白可以作为新的靶点 治疗心力衰竭。拟议研究的基本原理是为了更好地了解SUR2对 心肌细胞代谢，以控制心力衰竭时的能量消耗。为了证明这一假设， 我们将使用基因工程小鼠模型，下调SUR2的表达以及人类诱导的 ABCC9基因变异心脏患者的多能干细胞来源的心肌细胞 衰竭和心律失常表型。这将为我们提供一个独特的机会来证实调查结果。 来自动物和来自人类心肌细胞的基因。作为拟议工作的结果，我们预计 确定SUR2在啮齿动物和人心肌细胞中的细胞和生理作用。体内结合 转基因小鼠模型和人类衍生细胞有望垂直推进对 如何更好地操纵SUR2以达到治疗目的。

PROJECT SUMMARY/ABSTRACT The objectives of this proposal are to 1) nurture the development of Dr. Gregory Aubert to become a successful physician scientist investigator in the field of cardiovascular disease with focus on cardiac metabolism, and 2) to better outline the role of the sulfonylurea receptor 2 (SUR2) in the control of cardiomyocyte metabolism under physiological stressors, and more specifically in the development of heart failure. This application has been designed to help Dr. Aubert succeed in his transition to an independent investigator through 1) graduate level and junior faculty coursework in the Loyola Stritch School of medicine and Northwestern Clinical and Translational Sciences Institute and the Interdisciplinary Biological Sciences program 2) development of proficiency in new scientific methods such as human induced pluripotent stem cell (hiPSC) derived cardiomyocyte and gene editing, 3) improvement of skills in scientific communication and translational medicine through structured mentorship. Many current therapies for heart failure are directed at disturbances in the neurohormonal axis and do not directly target the cardiomyocyte. Evidence is emerging that alterations in myocyte energy metabolism and substrate utilization are key components of the heart failure development. Nonetheless, the exact mechanisms leading to this metabolic shift are not well delineated. Human genetic studies have identified mutations in the ABCC9 gene, which encodes SUR2, in the development of dilated cardiomyopathy and ventricular arrhythmias. Mice globally deleted for Abcc9/SUR2 develop heart failure in the neonatal window with a failure to transition normally to oxidative metabolism. Given the role of SUR2 and its partner proteins to modulate cardiac energetics, we believe that this protein could serve as a new target in the treatment of heart failure. The rationale for the proposed research is to better understand SUR2 regulation of cardiomyocyte metabolism in order to manipulate energy expenditure in heart failure. To prove this hypothesis, we will use a genetically engineered mouse model with downregulation of SUR2 as well as human induced pluripotent stem cells-derived cardiomyocytes derived from patients having ABCC9 genetic variants with heart failure and arrhythmia phenotypes. This will provide us with the unique opportunity to corroborate the findings from animals with those from human cardiomyocytes. As a consequence of the work proposed, we expect to determine the cellular and physiological role of SUR2 in rodent and human cardiomyocyte. Combining in vivo genetically modified mouse models and human derived cells is expected to vertically advance understanding of how SUR2 can be better manipulated for therapeutic purpose.