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：
9103283
负责人：
DANIEL PATRICK KELLY
金额：
$ 92.52万
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 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9103283
关键词：
Acetyl Coenzyme A Acetylation Address Animal Model Automobile Driving Bioenergetics Carbon Cardiac Cardiac Myocytes 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 Pathogenesis Pathologic Physiological Prevention strategy Process Protein Acetylation Proteins Proteomics Publishing Regulator Genes Role Route Sampling Series Source Staging Starvation Systems Biology Testing Tissues Transcript Ventricular Function base comparative design end stage disease exercise training 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 research study 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（由适用提供）：大量证据表明，在心力衰竭（HF）的发展过程中，心脏会经历线粒体燃料代谢和生物能学的急剧改变。具体而言，氧化主要燃料，脂肪酸的能力葡萄糖在心脏肥大的发展和心脏失败的过程中受到约束。在动物模型和人类中的研究表明，在HF的早期阶段，心肌高能磷酸盐储存的降低，为“能量饥饿”，收缩功能障碍和疾病进展的奇妙循环奠定了基础。迄今为止，大多数旨在描述驱动HF能量代谢演化的机制的研究是在最新阶段疾病中进行的，并专注于基因调节机制。此类研究的结果表明，线粒体肌细胞死亡和涉及线粒体能量转移的基因的宽度下调的改变改变了。但是，这些异常可能反映了最终不可逆的过程。在过去的几年中，我们开始进行研究，以阐明在定义明确的小鼠模型中，在病理重塑的早期途径中发生的能量代谢重塑事件。对于这些研究，我们采用了一种系统生物学方法，该方法由NHLBI支持的基于团队的资金计划（RFA-HL-10-002）支持。对代表病理学（压力超负荷）和自适应（运动训练）心脏肥大的心脏样本以及HF的早期阶段进行了综合转录组和代谢组学分析。对数据集的比较分析导致了一些令人惊讶的发现，这导致了以下假设：在压力超负荷的病理心脏重塑的早期阶段，从脂肪酸的缓解到酮酮利用率的心肌底物转变为在型乙酰含量的量含量均可用蛋白量的蛋白质蛋白质蛋白质蛋白质蛋白均取代蛋白质的稳定剂量，从而导致均取代蛋白质的含量。并有助于HF的发病机理。我们组建了一个多PIC团队来解决这一假设。在AIM 1中，我们将采用一种新的方法来定义线粒体蛋白乙酰化的化学计量，并在早期失败的小鼠心脏中确定其功能后果。在AIM 2中，我们将确定调节线粒体短链碳的导出对蛋白质乙酰化，底物代谢以及在正常，肥大和心脏失败的心脏中进行重塑的影响。 AIM 3旨在探索心肌燃料利用中慢性转移对心脏线粒体蛋白乙酰磷脂的影响，底物代谢以及在正常和失败的小鼠心脏中进行重塑。该项目的长期目标是确定与开发创新的代谢调节策略相关的新机制和治疗靶标，以预防和早期治疗心力衰竭。