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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：
10430277
负责人：
DANIEL PATRICK KELLY
金额：
$ 72.37万
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/10430277
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.

总结