A Genomic/Metabolomic Strategy to Characterize Cardiac Mitochondrial Dysfunction

表征心脏线粒体功能障碍的基因组/代谢组学策略

基本信息

批准号：
8241923
负责人：
DANIEL PATRICK KELLY
金额：
$ 72.7万
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：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241923
关键词：
Acute Address Animal Model Biogenesis Bioinformatics Biology Burn injury Candidate Disease Gene Cardiac Cardiovascular Diseases Cardiovascular system Chronic Data Set Defect Development Down-Regulation Engineering Exercise Fatty Acids Functional disorder Future Gene Targeting Genes Genomics Glucose Goals Health Heart Heart Hypertrophy Heart failure Hypertension Hypertrophy Informatics Lead Measurement Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Mus Muscle Cells Myocardial Infarction Myocardium Pathogenesis Pathologic Pathway interactions Perinatal Peroxisome Proliferator-Activated Receptors Physiological Plasma Prevention Process Respiratory physiology Severities Signal Transduction Staging Stress System Testing Therapeutic Tissues Transcription Coactivator Ventricular Remodeling Wild Type Mouse Work abstracting base comparative design gain of function loss of function metabolomics mitochondrial dysfunction mouse model novel therapeutic intervention oxidation preference prevent therapy development transcription factor

项目摘要

DESCRIPTION (provided by applicant): Despite significant advances in the treatment of cardiovascular disease over the past several decades, therapeutic approaches to prevent the pathologic myocardial remodeling processes that lead to heart failure, a worldwide health threat, are limited. Evidence is emerging that mitochondrial dysfunction contributes to the pathogenesis of heart failure. We have shown that the transcriptional coactivators, PPAR? transcriptional coactivator-1alpha and beta (PGC-1? and PGC-1?), are required for normal perinatal mitochondrial biogenesis and respiratory function in heart. The expression and activity of PGC-1? and several of its transcription factor targets (PPAR?, ERR?), are diminished in pathologic forms of cardiac hypertrophy and in the failing heart. Recent findings suggest that chronic deactivation of PGC-1 signaling becomes maladaptive, leading to mitochondrial dysfunction and heart failure. However, the specific PGC-1 target genes and pathways, relevant to progressive energy metabolic demise and contractile dysfunction in the failing heart remain unknown. This proposal is designed to test the hypothesis that dysregulated activity of processes downstream of PGC-1? and PGC-1? lead to mitochondrial dysfunction and contribute to the pathologic remodeling that leads to heart failure. It is also proposed that downregulation of a subset of PGC-1 targets, including those involved in fuel preference shifts, may be protective in the context of pathophysiological stress. To address this problem, we have assembled a multi-disciplinary team to use a systems approach, combining unbiased gene transcriptional and targeted, mass spectrometric-based metabolite profiling. The objective of Aim 1 will be to identify relevant dysregulated genes and altered metabolite profiles in the hearts of an inducible, cardiac-specific, PGC-1?/? loss-of-function mouse model of heart failure. In Aim 2, the dataset in Aim 1 will be compared with that generated for mice that have been genetically-engineered to model derangements in mitochondrial fuel burning, including selective blocks in mitochondrial FA and glucose oxidation, but normal cardiac function. In Aim 3, genomic and metabolomic profiling will be conducted with hearts of wild-type mice with: 1) physiologic (exercise-induced) cardiac hypertrophy; 2) compensated pathologic cardiac hypertrophy; and 3) decompensated cardiac hypertrophy (failing heart). Informatic-based comparative analysis of the datasets from Aims 1-3 will be used to generate a prioritized list of genes, metabolites, and corresponding metabolic pathways/processes that will serve as candidate signatures for mitochondrial derangements relevant to the development of pathologic cardiac metabolic and functional remodeling, to be further validated in Aim 4. The long-term goal of this project is to evaluate the efficacy of modulating the candidate pathways to maintain cardiac mitochondrial function as a new therapeutic approach for the prevention and treatment of heart failure. (End of Abstract)

描述（由申请人提供）：尽管过去几十年来心血管疾病的治疗取得了重大进展，但预防导致心力衰竭（全球健康威胁）的病理性心肌重塑过程的治疗方法仍然有限。越来越多的证据表明线粒体功能障碍导致心力衰竭的发病机制。我们已经证明转录共激活因子 PPAR？转录辅激活因子-1α和β（PGC-1？和PGC-1？）是正常围产期线粒体生物发生和心脏呼吸功能所必需的。 PGC-1的表达和活性？及其几个转录因子靶标（PPAR？、ERR？）在心脏肥大和心力衰竭的病理形式中减少。最近的研究结果表明，PGC-1 信号传导的慢性失活会导致适应不良，导致线粒体功能障碍和心力衰竭。然而，与衰竭心脏中进行性能量代谢消亡和收缩功能障碍相关的特定 PGC-1 靶基因和通路仍然未知。该提案旨在检验以下假设：PGC-1 下游过程的活性失调？和PGC-1？导致线粒体功能障碍并导致导致心力衰竭的病理重塑。还提出，PGC-1 靶标子集的下调，包括那些涉及燃料偏好转变的靶标，可能在病理生理应激背景下具有保护作用。为了解决这个问题，我们组建了一个多学科团队，使用系统方法，将公正的基因转录和基于质谱的靶向代谢物分析相结合。目标 1 的目标是确定可诱导的、心脏特异性的 PGC-1?/? 心脏中相关失调基因和改变的代谢物谱。心力衰竭功能丧失小鼠模型。在目标 2 中，目标 1 中的数据集将与经过基因工程改造的小鼠生成的数据集进行比较，以模拟线粒体燃料燃烧的紊乱，包括选择性阻断线粒体 FA 和葡萄糖氧化，但心脏功能正常。在目标 3 中，将对具有以下特征的野生型小鼠的心脏进行基因组和代谢组学分析：1) 生理性（运动诱发的）心脏肥大； 2）代偿性病理性心脏肥大； 3) 失代偿性心脏肥大（心脏衰竭）。对目标 1-3 的数据集进行基于信息的比较分析，将用于生成基因、代谢物和相应代谢途径/过程的优先列表，这些列表将作为与病理性心脏代谢和发展相关的线粒体紊乱的候选特征。功能重塑，将在目标 4 中进一步验证。该项目的长期目标是评估调节候选途径维持心脏线粒体功能的功效，作为预防和治疗的新治疗方法心力衰竭。（摘要完）