Metabolic Reprogramming of the Adult heart to a Regenerative State

成人心脏代谢重编程至再生状态

基本信息

批准号：
10562415
负责人：
Ahmed I Mahmoud
金额：
$ 41.71万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10562415
关键词：
Adult Angiogenic Factor Animals Birth Cardiac Cardiac Myocytes Cause of Death Cell Cycle Citric Acid Cycle Complex DNA Damage Data Development Dose EFRAC Electron Microscopy Electron Transport Embryo Endothelium Enzymes Exhibits Family suidae Fibrosis Genetic Transcription Glycolysis Heart Heart Transplantation Heart failure Human Infarction Injury Ischemia Knock-out Malonates Mass Spectrum Analysis Mediating Metabolic Metabolism Mitochondria Molecular Morbidity - disease rate Morphology Mus Myocardial Myocardial Infarction Myocardium Myofibroblast Natural regeneration Neonatal Nuclear RNA Operative Surgical Procedures Oxidation-Reduction Patients Physiology Pilot Projects Play Prevention Production Proliferating Public Health Publishing Reperfusion Injury Resolution Respiration Role Structure Succinate Dehydrogenase Testing Therapeutic Time Tissues Toxic effect Translations Transplantation Treatment Failure Vascularization Vertebrates angiogenesis cardiac regeneration cardioprotection cdc Genes cell type coronary fibrosis effective therapy experimental study fatty acid metabolism fatty acid oxidation heart damage heart function improved in vivo lipidomics metabolomics microscopic imaging mortality neonatal mice novel novel strategies novel therapeutic intervention novel therapeutics oxidative DNA damage porcine model postnatal programs regeneration following injury regeneration potential regenerative regenerative therapy response restoration transcription regulatory network transcriptome sequencing translational potential

项目摘要

Project Summary Heart failure with reduced ejection fraction is a major public health burden with high morbidity and mortality. Identifying novel approaches towards regenerating heart tissue has significant therapeutic potential for heart failure patients. Similar to lower vertebrates, neonatal mice can regenerate their hearts following injury for a brief window after birth. Remarkably, we recently discovered that inhibition of the mitochondrial enzyme succinate dehydrogenase (SDH) can promote adult cardiac regeneration following myocardial infarction (MI). Our results are distinct from the previous studies demonstrating a cardioprotective role for SDH inhibition against the redox insult during ischemia/reperfusion injury, as we demonstrate that SDH inhibition does not protect the heart against MI-induced infarction. The metabolic switch from glycolysis to fatty acid oxidation in the postnatal heart contributes to cardiomyocyte cell cycle exit and loss of endogenous cardiac regeneration potential. SDH, also known as mitochondrial complex II, plays a central role in regulating cellular metabolism as it is involved in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). Our recently published study demonstrates that inhibition of SDH by malonate treatment of adult mice following myocardial infarction stimulates cardiomyocyte proliferation, revascularization, and results in restoration of cardiac structure and function following infarction. Remarkably, our metabolite analysis following SDH inhibition demonstrates dynamic metabolic changes in the uninjured adult heart. Our overarching hypothesis is that SDH inhibition metabolically reprograms the adult heart to a regenerative state. To define the role of SDH in adult heart regeneration, we will pursue the following aims: 1) Elucidate the metabolic and cellular mechanisms underlying post-MI regeneration following SDH inhibition; 2) Define the molecular mechanisms by which SDH inhibition promotes post-MI regeneration; 3) Determine the role of SDH inhibition by malonate on regenerative potential following myocardial infarction in a porcine model. Our proposed experiments will define the mechanisms by which SDH inhibition promotes cardiac regeneration, as well as establish the therapeutic potential of SDH inhibition in large animal hearts which exhibit distinct physiology from the mouse heart. Collectively, our results reveal a novel role for SDH inhibition in promoting heart regeneration following myocardial infarction, and this proposal will generate important results that will lead to novel therapeutic strategies to regenerate the adult heart following infarction.

项目概要射血分数降低的心力衰竭是一个主要的公共卫生负担，发病率和死亡率很高。确定再生心脏组织的新方法对心脏具有巨大的治疗潜力失败患者。与低等脊椎动物类似，新生小鼠的心脏在短暂受伤后可以再生出生后的窗口。值得注意的是，我们最近发现线粒体酶琥珀酸的抑制脱氢酶（SDH）可以促进心肌梗塞（MI）后的成人心脏再生。我们的成果与之前证明 SDH 抑制氧化还原作用具有心脏保护作用的研究不同缺血/再灌注损伤期间的损伤，因为我们证明 SDH 抑制不能保护心脏对抗 MI 诱发的梗塞。出生后心脏从糖酵解到脂肪酸氧化的代谢转变有助于心肌细胞细胞周期的退出和内源性心脏再生潜力的丧失。 SDH，还有被称为线粒体复合物 II，在调节细胞代谢中发挥着核心作用，因为它参与三羧酸（TCA）循环和电子传输链（ETC）。我们最近发表的研究表明丙二酸治疗成年小鼠心肌梗塞后可抑制 SDH 刺激心肌细胞增殖、血运重建，并导致心脏结构的恢复和梗塞后的功能。值得注意的是，我们在 SDH 抑制后的代谢物分析表明动态未受伤的成人心脏的代谢变化。我们的总体假设是 SDH 抑制代谢将成人心脏重新编程至再生状态。为了定义 SDH 在成人心脏再生中的作用，我们将追求以下目标：1）阐明心肌梗死后再生的代谢和细胞机制 SDH 抑制后； 2) 明确SDH抑制促进心肌梗死后的分子机制再生; 3) 确定丙二酸抑制 SDH 对心肌细胞再生潜力的作用猪模型中的梗塞。我们提出的实验将定义 SDH 抑制的机制促进心脏再生，并确定 SDH 抑制在大型动物中的治疗潜力心脏表现出与小鼠心脏不同的生理机能。总的来说，我们的结果揭示了 SDH抑制促进心肌梗塞后心脏再生，该提案将产生重要的结果将导致梗死后成人心脏再生的新治疗策略。