Pathophysiological Regulation of Metabolism and Energy Use during Heart Failure

心力衰竭期间代谢和能量使用的病理生理调节

• 批准号: 10227925
• 负责人: Gregory Aubert
• 金额: $ 15.94万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227925
• 关键词: ABCC9 gene; Adult; Affect; Animals; Arrhythmia; Biological Sciences; Cantu syndrome; Cardiac; Cardiac Myocytes; Cardiomegaly; Cardiomyopathies; Cardiovascular Diseases; Cell Respiration; Cells; Clinical; Clinical Sciences; Communication; Cost of Illness; Data; Development; Dilated Cardiomyopathy; Disease; Down-Regulation; Energy Metabolism; Exhibits; Faculty; Failure; Gene Mutation; Generations; Genes; Genetic study; Genetically Engineered Mouse; Glucose; Glycolysis; Healthcare; Heart; Heart failure; Human; Human Genetics; Impairment; Individual; Institutes; Ischemia; Lead; Link; Mentorship; Metabolic; Metabolism; Methods; Mitochondria; Molecular; Mus; Muscle Cells; Mutation; Myocardial; Myocardial dysfunction; Myocardium; Neonatal; Outcome; Pathway interactions; Patients; Perinatal mortality demographics; Phenotype; Physicians; Physiological; Population; Potassium; Prevalence; Production; Proteins; RNA; Reactive Oxygen Species; Regulation; Research; Research Personnel; Rodent; Role; Scientist; Structure; Testing; Therapeutic; Tissues; Translational Research; United States; Variant; Ventricular Arrhythmia; Work; cardiogenesis; constriction; design; functional loss; genetic variant; heart function; heart metabolism; improved; in vivo; induced pluripotent stem cell; medical schools; metabolic abnormality assessment; mouse model; novel therapeutics; oxidation; physiologic stressor; pressure; prevent; programs; receptor; response; skills; stressor; sulfonylurea receptor; targeted treatment; therapy development; translational medicine

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.

项目总结/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生科学家研究员，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， 生理应激源，更具体地说，在心力衰竭的发展中。此应用程序已 旨在帮助奥伯特博士在研究生阶段成功地过渡到独立调查员 洛约拉·斯特里奇医学院和西北临床和 转化科学研究所和跨学科生物科学计划2）发展 熟练掌握新的科学方法，如人类诱导多能干细胞（hiPSC）衍生 心肌细胞和基因编辑，3）提高科学交流和转化医学技能 通过结构化的指导。许多目前用于心力衰竭的疗法针对的是在心血管系统中的紊乱。 神经激素轴，不直接靶向心肌细胞。有证据表明， 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还没有得到很好的描述。人类遗传 研究已经确定了ABCC9基因的突变，该基因编码SUR2， 心肌病和室性心律失常。Abcc9/SUR2整体缺失的小鼠在对照组中发生心力衰竭。 新生儿窗口期未能正常过渡到氧化代谢。考虑到SUR2的作用及其 我们认为，这种蛋白质可以作为一个新的靶点， 心力衰竭的治疗这项研究的基本原理是为了更好地了解SUR2对 心肌细胞代谢，以便操纵心力衰竭中的能量消耗。为了证明这个假设， 我们将使用一种基因工程小鼠模型，该模型下调了SUR2以及人类诱导的SUR2表达。 多能干细胞衍生的心肌细胞，其来源于具有ABCC9遗传变体的心脏病患者， 失败和心律失常表型。这将为我们提供一个独特的机会来证实调查结果 和人类心肌细胞的细胞。作为拟议工作的结果，我们希望 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衍生细胞有望垂直推进对 如何更好地操纵SUR2用于治疗目的。

项目成果

Fecal microbiome transplantation and tributyrin improves early cardiac dysfunction and modifies the BCAA metabolic pathway in a diet induced pre-HFpEF mouse model.

• DOI: 10.3389/fcvm.2023.1105581
• 发表时间: 2023
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Hatahet, Jomana;Cook, Tyler M.;Bonomo, Raiza R.;Elshareif, Nadia;Gavini, Chaitanya K.;White, Chelsea R.;Jesse, Jason;Mansuy-Aubert, Virginie;Aubert, Gregory
• 通讯作者: Aubert, Gregory