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：
10296253
负责人：
DANIEL PATRICK KELLY
金额：
$ 74.34万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10296253
关键词：
Animal Model Bypass Carbon Cardiac Cardiac Myocytes Cardiac development Cardiomyopathies ChIP-seq Chronic Coenzyme A Complex DHODH gene Development Diagnostic Disease Down-Regulation Echocardiography Energy-Generating Resources Enzymes Equilibrium Event Fatty Acids Functional disorder Funding Gene Deletion Generations Genetically Engineered Mouse Genomics Glucose Growth Heart Heart Hypertrophy Heart failure Homeostasis Human Hypertrophy Isotopes Ketone Bodies Left Link Maintenance Mass Spectrum Analysis Measures Metabolic Mitochondria Modeling Mus Mutation NADH dehydrogenase (ubiquinone)NCOR1 gene NRIP1 gene Nodal Oxidants Oxidation-Reduction Oxides Palmitates Pathogenesis Pathologic Pathway interactions Pattern Peroxisome Proliferator-Activated Receptors Phenotype Physiologic intraventricular pressure Process Production Proteins Proteomics Pyrimidine RNA immunoprecipitation sequencing Respiratory physiology Role Series Source Starvation Structure Supplementation Testing Ubiquinone Ventricular Ventricular Dysfunction Work base cardiogenesis chromatin immunoprecipitation cofactor comparative constriction deep sequencing design dihydroorotate end stage disease fatty acid oxidation global health heart function long chain fatty acid metabolomics novel novel therapeutic intervention oxidation preservation pressure prevent respiratory response therapeutic candidate

项目摘要

SUMMARY Current therapies for heart failure (HF) are largely directed at maladaptive extra-cardiac neurohormonal circuits in a “one size fits all” approach. There is a significant unmet need for mechanism-based therapies directly targeting the heart during early stages of HF. Increasing evidence has shown that during the development of heart failure, mitochondrial generation of ATP becomes dysregulated. A well-established metabolic signature of the failing heart is a shift from using fatty acids as the chief fuel source of the normal heart, to other fuels such as glucose. This fuel shift occurs early in the development of cardiac hypertrophy and failure. However, the potential linkage of this cardiac fuel switch to the progressive diminution in mitochondrial respiratory function and ATP producing capacity during the development of HF has not been established beyond a mere association. During the current funding period, we have made a series of discoveries that support the premise that disturbances in cardiac fatty acid oxidation (FAO) contribute to mitochondrial energetic dysfunction and the development of HF including: 1) identification of distinct “bottlenecks” in the terminal steps of the FAO pathway setting the stage for depletion of key cofactors such as Coenzyme A (CoA) and diversion of reducing equivalents away from complex I of the electron transport chain; 2) the ketone body, 3-hydroxybutryate (3OHB), an efficient cardiac fuel that bypasses long-chain FAO, reduces cardiac remodeling and ventricular dysfunction in small and large animal models of HF; and 3) increasing cardiac mitochondrial oxidative capacity, including FAO flux, by cardiac-specific deletion of the gene encoding RIP140 (Nrip1) prevents cardiac hypertrophic growth and reduces cardiac remodeling and dysfunction caused by pressure overload in mice. These findings have led to the central hypotheses of this multi-PI R01 renewal proposal: Downregulation of FAO in the hypertrophied heart results in bottlenecking within the -oxidation spiral leading to reduced capacity for mitochondrial ATP production and; reduced FAO flux sets the stage for utilization of carbon sources from glucose and other sources in anabolic pathways necessary for cardiac hypertrophic growth. These hypotheses will be tested by two aims. In Aim 1, we will conduct in-depth assessment of the cardiac functional, mitochondrial, proteomic and genomic response of wild-type, csRIP140-/- (high FAO), and csPPAR-/- (low FAO) mice during development of HF in mice. Aim 2 is designed to determine the mechanisms whereby RIP140 deficiency defends against pathological cardiac hypertrophic growth. The long-term objectives of the proposed work are to define the mechanistic events leading to mitochondrial energetic collapse in the failing heart and to identify nodal regulatory points that could serve as candidate therapeutic strategies aimed at re-balancing fuel utilization and enhancing mitochondrial ATP-producing capacity aimed at the early stages of heart failure.

概括目前心力衰竭 (HF) 的治疗主要针对适应不良的心外神经激素回路在“一刀切”的方法中，对直接基于机制的疗法的需求尚未得到满足。越来越多的证据表明，在心力衰竭的早期阶段，以心脏为目标。心力衰竭时，线粒体 ATP 生成失调。心脏衰竭是从使用脂肪酸作为正常心脏的主要燃料来源转向其他燃料，例如这种燃料转移发生在心脏肥大和衰竭的早期。这种心脏燃料转换与线粒体呼吸功能逐渐减弱的潜在联系 HF 发展过程中 ATP 产生能力尚未建立，超出了单纯的关联。在当前的资助期间，我们取得了一系列发现，支持以下前提：心脏脂肪酸氧化 (FAO) 紊乱会导致线粒体能量功能障碍和 HF 的发展包括： 1) 识别粮农组织路径最后步骤中的独特“瓶颈” 为辅酶 A (CoA) 等关键辅因子的消耗和还原当量的转移奠定基础远离电子传递链的复合物I；2)酮体，3-羟基丁酸酯(3OHB)，一种高效的酮体。绕过长链FAO的心脏燃料，减少小和小心脏的心脏重塑和心室功能障碍心力衰竭的大型动物模型；3) 增加心脏线粒体氧化能力，包括FAO通量，通过心脏特异性删除编码 RIP140 (Nrip1) 的基因可防止心脏肥大性生长并减少这些发现导致了小鼠压力超负荷引起的心脏重塑和功能障碍。该多PI R01更新提案的假设：肥大心脏结果中FAO的下调 -氧化螺旋内的瓶颈导致线粒体 ATP 能力降低生产和减少粮农组织通量为利用葡萄糖和碳源奠定了基础这些假设将是心脏肥大生长所需的合成代谢途径的其他来源。通过两个目标进行测试在目标 1 中，我们将对心脏功能、线粒体、野生型、csRIP140-/-（高FAO）和csPPARα-/-（低FAO）小鼠的蛋白质组和基因组反应目的 2 旨在确定 RIP140 缺陷的防御机制。防止病理性心脏肥厚生长拟议工作的长期目标是定义。导致衰竭心脏中线粒体能量崩溃的机械事件并识别节点监管点可以作为候选治疗策略，旨在重新平衡燃料利用和增强线粒体 ATP 生成能力，针对心力衰竭的早期阶段。