Metabolic Reprogramming of the Adult heart to a Regenerative State

成人心脏代谢重编程至再生状态

• 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
• 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

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.

项目摘要 射血分数降低的心力衰竭是一个主要的公共卫生负担，具有高发病率和死亡率。 确定再生心脏组织的新方法对心脏病具有重要的治疗潜力。 失败的病人与低等脊椎动物相似，新生小鼠在短暂的损伤后可以再生心脏。 出生后的窗口值得注意的是，我们最近发现抑制线粒体琥珀酸酶 脱氢酶（SDH）可促进心肌梗死（MI）后成人心脏再生。我们的结果 与以前的研究不同，证明SDH抑制对氧化还原的心脏保护作用。 在缺血/再灌注损伤过程中的损伤，因为我们证明了SDH抑制不保护心脏 心肌梗死的治疗出生后心脏糖酵解到脂肪酸氧化的代谢转换 导致心肌细胞细胞周期退出和内源性心脏再生潜力丧失。此外， 称为线粒体复合物II，在调节细胞代谢中起着核心作用，因为它参与了 三羧酸（TCA）循环和电子传递链（ETC）。我们最近发表的研究 证明了心肌梗塞后成年小鼠的丙二酸盐治疗对SDH的抑制 刺激心肌细胞增殖、血管再生，并导致心脏结构的恢复， 梗死后的功能。值得注意的是，我们的代谢物分析后SDH抑制证明动态 未受损伤的成人心脏的代谢变化。我们的首要假设是SDH抑制代谢 将成年人的心脏重新编程到再生状态为了明确SDH在成人心脏再生中的作用，我们将 本研究的主要目的是：1）阐明心肌梗死后再生的代谢和细胞机制 2）定义SDH抑制促进MI后心肌梗死的分子机制 3）确定丙二酸盐对心肌缺血后SDH抑制对再生电位的作用。 在猪模型中的梗塞。我们提出的实验将确定SDH抑制的机制， 促进心脏再生，以及在大型动物中建立SDH抑制的治疗潜力 显示出与小鼠心脏不同的生理学的心脏。总的来说，我们的研究结果揭示了一个新的作用， SDH抑制促进心肌梗死后心脏再生，这一建议将产生 重要的结果，将导致新的治疗策略，再生成人心脏梗死后。