A Genomic/Metabolomic Strategy to Characterize Cardiac Mitochondrial Dysfunction

描述（由申请人提供）： 尽管在过去的几十年中在心血管疾病的治疗方面取得了显著的进展，但是用于预防导致心力衰竭的病理性心肌重塑过程的治疗方法是有限的，心力衰竭是一种全球性的健康威胁。有证据表明，线粒体功能障碍有助于心力衰竭的发病机制。我们已经表明，转录辅激活因子，过氧化物酶体增殖物激活受体？转录辅激活因子-1 α和β（PGC-1？和PGC-1？），是正常围产期线粒体生物合成所必需的， 心脏呼吸功能。PGC-1的表达和活性？及其几种转录因子靶点（PPAR？，错误？），在病理性心脏肥大和心力衰竭中减少。最近的研究结果表明，PGC-1信号的慢性失活变得适应不良，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死亡和收缩功能障碍相关的特定PGC-1靶基因和途径仍然未知。这项建议的目的是测试的假设，失调的活动过程下游的PGC-1？PGC-1？导致线粒体功能障碍并促成导致心力衰竭的病理性重塑。还提出下调PGC-1靶标的子集，包括参与燃料偏好转变的那些，在病理生理应激的背景下可能是保护性的。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，结合无偏见的基因转录和有针对性的，基于质谱的代谢物分析。目的1的目的是确定相关的失调基因和改变代谢产物的档案在心脏的诱导，心脏特异性，PGC-1？/？心力衰竭的功能丧失小鼠模型。在目标2中，目标1中的数据集将与已经基因工程改造以模拟线粒体燃料燃烧紊乱的小鼠生成的数据集进行比较，包括线粒体FA和葡萄糖氧化的选择性阻断，但心脏功能正常。在目标3中，将用具有以下情况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（运动诱导的）心脏肥大; 2）代偿性病理性心脏肥大;和3）失代偿性心脏肥大（心力衰竭）。对目标1-3的数据集进行基于信息的比较分析，以生成基因、代谢物和相应代谢途径/过程的优先列表，这些基因、代谢物和代谢途径/过程将作为与病理性心脏代谢和功能重塑发展相关的线粒体紊乱的候选特征，并在目标4中进一步验证。该项目的长期目标是评估调节候选途径以维持心脏线粒体功能作为预防和治疗心力衰竭的新治疗方法的疗效。 (End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)