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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.