Protein acetylation-dependent fatty acid metabolic dysfunction in HFpEF

HFpEF 中蛋白质乙酰化依赖性脂肪酸代谢功能障碍

• 批准号: 10369549
• 负责人: Dan Tong
• 金额: $ 14.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369549
• 关键词: 3-Hydroxyacyl-CoA dehydrogenase; Acetyl-CoA C-Acetyltransferase; Acetylation; Acetyltransferase; Agonist; Attenuated; Biological Assay; Cardiac; Cardiovascular Manifestation; Cardiovascular system; Clinical; Coenzyme A; Complement; Coupled; Data; Deacetylase; Defect; Diabetes Mellitus; EFRAC; Enoyl-CoA Hydratase; Enzymes; Equilibrium; Failure; Fatty Acids; Foundations; Functional disorder; Health Expenditures; Heart; Heart failure; High Fat Diet; Human; Hypertension; Immunoprecipitation; Impairment; In Vitro; Investigation; Knock-out; Knowledge; Laboratories; Link; Lysine; Mass Spectrum Analysis; Mechanical Stress; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic stress; Metabolic syndrome; Metabolism; Mitochondria; Mitochondrial Proteins; Morbidity - disease rate; Mus; Myocardium; NG-Nitroarginine Methyl Ester; Neurodegenerative Disorders; Nicotinamide adenine dinucleotide; Nitric Oxide Synthase; Obesity; Oral; Pathogenesis; Pathway interactions; Patients; Phenotype; Physicians; Post-Translational Protein Processing; Pre-Clinical Model; Protein Acetylation; Proteins; Proteomics; Research; Research Personnel; Research Project Grants; Rodent; Role; Scheme; Scientist; Secondary to; Sirtuins; Source; Stress; Syndrome; Testing; Therapeutic Effect; Tissues; Training; Treatment Failure; Work; acyl-CoA dehydrogenase; arginine methyl ester; base; career; effective therapy; experimental study; fatty acid oxidation; hypertensive; insight; loss of function; mitochondrial dysfunction; mortality; mouse model; nicotinamide-beta-riboside; novel; novel therapeutics; preservation; protein function; skills; therapeutic target

Project Summary Heart failure with preserved ejection fraction (HFpEF) accounts for ≈50% of all patients with heart failure, and is associated with significant morbidity, mortality, and health care expenditures. Yet, no effective treatment for HFpEF has been identified. Commonly coexisting with other metabolic diseases, HFpEF is considered the cardiovascular manifestation of a systemic metabolic disturbance. However, little is known about its underlying mechanisms. Our laboratory recently developed and validated a novel mouse model that faithfully recapitulates most clinical features of human HFpEF. Using this novel mouse model, I discovered significant mitochondrial dysfunction in HFpEF myocardium, which is associated with mitochondrial protein hyperacetylation, a key post- translational modification known to regulate enzymatic activities. This led to our central hypothesis that protein hyperacetylation is a reversible driver of mitochondrial dysfunction and metabolic remodeling in HFpEF and could serve as a meaningful therapeutic target. In this proposal, we aim to (1) Determine the role of Sirtuin 3, the major mitochondrial deacetylase, in regulating mitochondrial function and HFpEF pathogenesis; (2) Identify specific targets through which hyperacetylation impacts mitochondrial function in HFpEF; (3) Determine the therapeutic effect of modulating protein acetylation on HFpEF mitochondrial function and cardiac phenotype. Collectively, these studies will have a meaningful impact on our understanding of HFpEF pathophysiology and potentially unveil novel therapy to effectively treat HFpEF. Furthermore, work proposed here, coupled with a comprehensive training plan, will provide me with the additional knowledge and skills required to launch my career as a successful and fully independent physician-scientist.

项目概要 射血分数保留的心力衰竭 (HFpEF) 约占所有心力​​衰竭患者的 50%，并且 与显着的发病率、死亡率和医疗保健支出相关。但目前尚无有效治疗方法 HFpEF 已被识别。 HFpEF 通常与其他代谢性疾病共存，被认为是 全身代谢紊乱的心血管表现。然而，人们对它的底层知之甚少 机制。我们的实验室最近开发并验证了一种新颖的小鼠模型，该模型忠实地再现了 人类 HFpEF 的大部分临床特征。使用这种新颖的小鼠模型，我发现了重要的线粒体 HFpEF 心肌功能障碍与线粒体蛋白过度乙酰化有关，线粒体蛋白过度乙酰化是治疗后的关键 已知调节酶活性的翻译修饰。这导致了我们的中心假设：蛋白质 过度乙酰化是 HFpEF 中线粒体功能障碍和代谢重塑的可逆驱动因素，并且可能 作为有意义的治疗靶点。在本提案中，我们的目标是 (1) 确定 Sirtuin 3 的作用，它是主要的 线粒体脱乙酰酶，调节线粒体功能和 HFpEF 发病机制； (2) 确定具体的 HFpEF 中超乙酰化影响线粒体功能的目标； (3)确定治疗方案 调节蛋白质乙酰化对 HFpEF 线粒体功能和心脏表型的影响。总的来说， 这些研究将对我们对 HFpEF 病理生理学的理解产生有意义的影响，并有可能 推出有效治疗 HFpEF 的新疗法。此外，这里提出的工作以及全面的 培训计划，将为我提供开展职业生涯所需的额外知识和技能 成功且完全独立的医师科学家。