Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure

心脏肥大和衰竭的能量状态和代谢重塑

基本信息

批准号：
10704664
负责人：
QINGLIN YANG
金额：
$ 49万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-14 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704664
关键词：
Acute Adult Aerobic Animals Aortic Valve Stenosis Biogenesis Cardiac Cardiac Myocytes Cardiomyopathies Cause of Death Congestive Heart Failure Cytosol Defect Development Diabetes Mellitus Dilated Cardiomyopathy Disease Energy consumption Etiology Fatty Acids Fibroblasts Foundations Functional disorder Glucose Heart Heart Hypertrophy Heart failure Homeostasis Hypertension Hypertrophy Impairment Inherited Ketone Bodies Knowledge Lead Left Left ventricular structure Mediating Metabolic Metabolism Mitochondria Mitochondrial Diseases Modeling Molecular Machines Morphology Multienzyme Complexes Mus Mutation Myocardial Myocardial dysfunction Neuromuscular Diseases Oxidative Phosphorylation Pathologic Patient Care Patients Performance Physiologic intraventricular pressure Play Production Pump Rattus Respiration Risk Factors Role Side Stress Structure System Testing Therapeutic Virulence Factors advanced disease ascending aorta effective intervention effective therapy efficacy testing embryo culture experimental study gene therapy heart function improved innovation insight mortality new therapeutic target novel oligomycin sensitivity-conferring protein oxidation pre-clinical preference pressure protective effect targeted treatment therapeutic development

项目摘要

Pathological stresses, such as pressure overload in the left ventricles of patients with hypertension and aortic valve stenosis, cause cardiac hypertrophy, a major risk factor of congestive heart failure. Hypertrophic and failing hearts shift substrate utilization preference from fatty acids to glucose, ketone bodies, and others. However, the interplay between the energetic state and the mitochondrial/metabolic remodeling in the hypertrophic and failing remains incompletely understood. Most of the past studies are based on models with confounding conditions. F1Fo-ATP synthase is an essential enzyme complex that generates ATP in mitochondria, thus playing a central role in cellular energetics. Genetic defects of F1Fo-ATP synthase are rare but deadly because of dilated cardiomyopathy and neuromuscular disorders. How those patients with partial F1Fo-ATP synthase deficiencies respond to pathological stresses is unclear. It is documented that F1Fo-ATP synthase is impaired in pathological hearts from patients and animals. Our recent study revealed that enhancing F1Fo-ATP synthase structure/function using gene therapy restored cardiac function in the hypertrophied hearts, corroborating the concept of targeting F1Fo-ATP synthase as a novel protective therapy for heart failure. Our prior studies demonstrated that mice lacking F1Fo-ATP synthase assembly factors, such as ATPAF1, lead to F1Fo-ATP synthase deficiencies with cardiomyopathy. Therefore, our central hypothesis is that enhancing F1Fo-ATP synthase capacity to facilitate ATP production efficiency will mitigate mitochondrial disorders and the ensued cardiac hypertrophy and failure. We propose to test the central hypothesis with two aims. In aim 1, we will test that the F1Fo-ATP synthase deficiency is an amendable pathogenic factor in heart failure progression. Experiments will provide evidence to support that partial F1Fo- ATP synthase deficiency contributes to the pathological progression of heart failure, and gene therapies correcting the deficiency will slow the heart failure progression. In aim 2, we will define how F1Fo-ATP synthase capacities directly correlate to mitochondrial homeostasis and metabolic remodeling in cardiomyocytes of the adult heart. Therefore, this proposed project will provide definitive evidence to support innovative gene therapy and define the underpinning mechanisms. The proposed study will yield novel insights into the primary mechanisms underlying metabolic remodeling in cardiac pathological hypertrophy progression. The preclinical animal study will lay the groundwork for innovative gene therapies, which will significantly impact patient care.

病理应激，例如高血压和主动脉疾病患者左心室压力超负荷瓣膜狭窄，引起心脏肥大，是充血性心力衰竭的主要危险因素。肥厚型和衰竭的心脏将底物利用偏好从脂肪酸转向葡萄糖、酮体等。然而，能量状态与线粒体/代谢重塑之间的相互作用肥大和衰弱的原因仍不完全清楚。过去的大部分研究都是基于模型混杂条件。 F1Fo-ATP 合酶是一种必需的酶复合物，可在线粒体，因此在细胞能量学中发挥着核心作用。 F1Fo-ATP 合酶的遗传缺陷很少见但由于扩张型心肌病和神经肌肉疾病而致命。那些患有部分疾病的患者如何 F1Fo-ATP 合酶缺陷对病理应激的反应尚不清楚。据记载，F1Fo-ATP 患者和动物的病理性心脏中合酶受损。我们最近的研究表明使用基因治疗增强 F1Fo-ATP 合酶结构/功能可恢复心脏功能肥大的心脏，证实了针对 F1Fo-ATP 合酶作为新型保护性疗法的概念用于心力衰竭。我们之前的研究表明，小鼠缺乏 F1Fo-ATP 合酶组装因子，例如如 ATPAF1，导致 F1Fo-ATP 合酶缺陷并导致心肌病。因此，我们的中心假设是增强 F1Fo-ATP 合酶能力以促进 ATP 生产效率将减轻线粒体疾病以及随之而来的心脏肥大和衰竭。我们建议测试中央有两个目标的假设。在目标 1 中，我们将测试 F1Fo-ATP 合酶缺陷是否是可修正的心力衰竭进展的致病因素。实验将提供证据支持部分 F1Fo- ATP合酶缺乏导致心力衰竭的病理进展和基因治疗纠正缺陷将减缓心力衰竭的进展。在目标 2 中，我们将定义 F1Fo-ATP 如何合酶能力与线粒体稳态和代谢重塑直接相关成人心脏的心肌细胞。因此，该拟议项目将提供明确的证据来支持创新基因疗法并定义基础机制。拟议的研究将产生新的见解探究心脏病病理性肥厚进展中代谢重塑的主要机制。临床前动物研究将为创新基因疗法奠定基础，这将显着影响患者护理。