Probing the Role of Mitochondrial Short-chain Carbon Homeostasis in the Hypertrophied and Failing Heart

探讨线粒体短链碳稳态在肥厚和衰竭心脏中的作用

基本信息

批准号：
9247800
负责人：
DANIEL PATRICK KELLY
金额：
$ 24.71万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247800
关键词：
Acetyl Coenzyme A Acetylation Address Animal Model Automobile Driving Bioenergetics Carbon Cardiac Cardiac Myocytes Cardiac development Cessation of life Chronic Data Set Development Disease Disease Progression Down-Regulation Energy-Generating Resources Etiology Event Fatty Acids Functional disorder Funding Gene Targeting Genes Glucose Goals Heart Heart Hypertrophy Heart failure Homeostasis Human Hypertension Hypertrophy Ketone Bodies Ketones Metabolic Metabolism Mitochondria Mitochondrial Proteins Mus Myocardial National Heart, Lung, and Blood Institute Nutraceutical Oxidative Phosphorylation Oxides Pathogenesis Pathologic Physiological Prevention strategy Process Protein Acetylation Proteins Proteomics Publishing Regulator Genes Role Route Sampling Series Source Starvation Systems Biology Testing Tissues Transcript Ventricular Function base cardiogenesis comparative design end stage disease exercise training experimental study fatty acid oxidation global health innovation inorganic phosphate knockout gene metabolomics mouse model new therapeutic target novel strategies novel therapeutic intervention oxidation pressure prevent protein function public health relevance stoichiometry therapeutic target transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Significant evidence indicates that during the development of heart failure (HF) the heart undergoes dramatic alterations in mitochondrial fuel metabolism and bioenergetics. Specifically, the capacity for oxidizing the chief fuels, fatty acids and glucose, becomes constrained during the development of cardiac hypertrophy, and in the failing heart. Studies in animal models and in humans have shown that a reduction in myocardial high-energy phosphate stores occurs in early stages of HF, setting the stage for a vicious cycle of "energy-starvation", contractile dysfunction, and progression of disease. To date, most studies aimed at delineating mechanisms driving the energy metabolic derangements of HF have been conducted in late stage disease, and have focused on gene regulatory mechanisms. The results of such studies have pointed to altered mitochondrial function, cardiac myocyte death, and widespread downregulation of genes involved in mitochondrial energy transduction. However, it is likely that many of these abnormalities reflect end-stage irreversible processes. Over the past several years, we have embarked on studies to elucidate energy metabolic remodeling events that occur in early stages of pathologic remodeling in route to HF in well-defined mouse models. For these studies, we employed a systems biology approach supported by an NHLBI-supported team-based funding initiative (RFA-HL-10-002). Integrated transcriptomic and metabolomics profiling was conducted on heart samples representing pathologic (pressure overload) and adaptive (exercise training) forms of cardiac hypertrophy, and in the early stages of HF. Comparative analysis of the datasets led to several surprising findings that have led to the hypothesis that during the early stages of pathologic cardiac remodeling caused by pressure overload, a myocardial substrate shift from reliance on fatty acids to ketone utilization sets the stage for expansion of the mitochondrial acetyl-CoA pool resulting in hyperacetylation of mitochondrial proteins, further reducing capacity for fuel oxidation and contributing to the pathogenesis of HF. We have assembled a multi-PI team to address this hypothesis. In Aim 1, we will employ a novel approach to define the stoichiometry of mitochondrial protein acetylation, and determine its functional consequences, in the early stage failing mouse heart. In Aim 2, we will determine the impact of modulating mitochondrial short-chain carbon export on protein acetylation, substrate metabolism, and remodeling in the normal, hypertrophied, and failing heart. Aim 3 is designed to explore the impact of chronic shifts in myocardial fuel utilization on cardiac mitochondrial protein acetylatio, substrate metabolism, and remodeling in the normal and failing mouse heart. The long-term goal of this project is to identify new mechanisms and therapeutic targets relevant to the development of innovative metabolic modulatory strategies for the prevention and early-stage treatment of heart failure.

描述（由申请人提供）：重要证据表明，在心力衰竭（HF）的发展过程中，心脏的线粒体燃料代谢和生物能量学发生了巨大的变化，具体来说，氧化主要燃料脂肪酸的能力。动物模型和人类研究表明，在心力衰竭的早期阶段，心肌高能磷酸盐储存量会减少，从而为恶性病变奠定了基础。迄今为止，大多数旨在描述心力衰竭能量代谢紊乱机制的研究都是在疾病晚期进行的，并集中在基因调控机制上。这样的研究指出线粒体功能改变、心肌细胞死亡以及参与线粒体能量转导的基因广泛下调。然而，这些异常可能反映了在过去几年中的终末期不可逆过程。研究旨在阐明在明确的小鼠模型中发生于心力衰竭病理重塑早期阶段的能量代谢重塑事件。在这些研究中，我们采用了由 NHLBI 支持的团队资助计划支持的系统生物学方法。 (RFA-HL-10-002) 对代表病理性（压力超负荷）和适应性（运动训练）形式的心脏肥大的心脏样本进行了综合转录组学和代谢组学分析，并在心力衰竭的早期阶段进行了数据集的比较分析。导致了一些令人惊讶的发现，这些发现导致了这样的假设：在压力超负荷引起的病理性心脏重塑的早期阶段，心肌底物从依赖脂肪酸转向酮利用奠定了基础线粒体乙酰辅酶A库的扩张导致线粒体蛋白质过度乙酰化，进一步降低燃料氧化能力并促进心力衰竭的发病机制，我们已经组建了一个多PI团队来解决这一假设。一种定义线粒体蛋白乙酰化化学计量并确定其功能后果的新方法，在目标 2 中，我们将确定调节线粒体的影响。短链碳输出对正常、肥大和衰竭心脏中蛋白质乙酰化、底物代谢和重塑的影响目标 3 旨在探索心肌燃料利用的慢性变化对心脏线粒体蛋白质乙酰化、底物代谢和重塑的影响。该项目的长期目标是确定与开发创新代谢调节策略相关的新机制和治疗靶点，以预防和早期治疗心力衰竭。