Pathophysiological Regulation of Metabolism and Energy Use during Heart Failure

项目概要/摘要 该提案的目标是 1) 培养 Gregory Aubert 博士成为一名成功的 心血管疾病领域的医师科学家研究员，重点关注心脏代谢，以及 2) 更好地概述了磺酰脲受体 2 (SUR2) 在控制心肌细胞代谢中的作用 生理压力源，更具体地说是心力衰竭的发展。此应用程序已 旨在帮助奥伯特博士通过 1) 研究生阶段成功过渡为独立研究者 洛约拉斯特里奇医学院和西北临床医学院的初级教师课程 转化科学研究所和跨学科生物科学项目 2) 的发展 熟练掌握新的科学方法，例如人类诱导多能干细胞 (hiPSC) 衍生的 心肌细胞和基因编辑，3）科学传播和转化医学技能的提高 通过结构化的指导。目前许多心力衰竭的治疗方法都是针对心律失常的。 神经激素轴，不直接针对心肌细胞。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展的关键组成部分。 尽管如此，导致这种代谢转变的确切机制尚不清楚。人类遗传 研究发现，编码 SUR2 的 ABCC9 基因发生突变，与扩张性扩张的发生有关。 心肌病和室性心律失常。因 Abcc9/SUR2 基因而被全球删除的小鼠在 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，我们相信这种蛋白可以作为一个新的靶点 治疗心力衰竭。拟议研究的基本原理是为了更好地了解 SUR2 的调节 心肌细胞代谢以控制心力衰竭时的能量消耗。为了证明这个假设， 我们将使用下调 SUR2 以及人类诱导的基因工程小鼠模型 多能干细胞衍生的心肌细胞，源自患有ABCC9基因变异的心脏患者 衰竭和心律失常表型。这将为我们提供独特的机会来证实研究结果 来自动物的心肌细胞和来自人类心肌细胞的心肌细胞。作为拟议工作的结果，我们期望 确定 SUR2 在啮齿动物和人类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来源的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.