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

• 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
• 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

 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，心脏经历线粒体燃料代谢和生物能量学的显著改变。具体来说，氧化主要燃料脂肪酸的能力 和葡萄糖，在心脏肥大的发展过程中以及在衰竭的心脏中受到限制。在动物模型和人类中的研究表明，在HF的早期阶段发生心肌高能磷酸盐储存的减少，为“能量饥饿”、收缩功能障碍和疾病进展的恶性循环奠定了基础。迄今为止，大多数旨在描述HF能量代谢紊乱的机制的研究都是在晚期疾病中进行的，并且集中在基因调控机制上。这些研究的结果指出了线粒体功能的改变、心肌细胞死亡和参与线粒体能量转导的基因的广泛下调。然而，这些异常中的许多可能反映了终末期不可逆过程。在过去的几年里，我们已经开始研究，以阐明在明确定义的小鼠模型中，在HF途径中的病理性重塑的早期阶段发生的能量代谢重塑事件。对于这些研究，我们采用了由NHLBI支持的基于团队的资助计划（RFA-HL-10-002）支持的系统生物学方法。对代表心脏肥大的病理性（压力超负荷）和适应性（运动训练）形式以及HF早期阶段的心脏样本进行整合转录组学和代谢组学分析。对数据集的比较分析导致了几个令人惊讶的发现，这些发现导致了以下假设：在由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到酮利用的转变为线粒体乙酰辅酶A库的扩张奠定了基础，导致线粒体蛋白的过度乙酰化，进一步降低燃料氧化的能力并促进HF的发病。我们已经组建了一个多PI团队来解决这个假设。在目标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，并确定其功能的后果，在早期衰竭小鼠心脏。在目标2中，我们将确定调节线粒体短链碳输出对正常、肥厚和衰竭心脏中蛋白质乙酰化、底物代谢和重塑的影响。目的3探讨心肌能量利用的慢性变化对正常和衰竭小鼠心脏线粒体蛋白乙酰化、底物代谢和重构的影响。该项目的长期目标是确定与开发用于预防和早期治疗心力衰竭的创新代谢调节策略相关的新机制和治疗靶点。