A Genomic/Metabolomic Strategy to Characterize Cardiac Mitochondrial Dysfunction

描述(由申请人提供)： 尽管心血管疾病的治疗在过去几十年中取得了重大进展，但预防导致心力衰竭的病理性心肌重构过程的治疗方法有限，心力衰竭是一个世界性的健康威胁。越来越多的证据表明，线粒体功能障碍与心力衰竭的发病机制有关。我们已经证明了转录共激活因子，PPAR？转录共激活因子-1α和β(PGC-1？和PGC-1)，是围产期正常的线粒体生物发生和心脏呼吸功能所必需的。PGC-1、PGC-1的表达和活性。它的几个转录因子靶标(PPAR？，ERR？)在心肌肥厚的病理形式和衰竭的心脏中都会减少。最近的研究结果表明，PGC-1信号的慢性失活变得不适应，导致线粒体功能障碍和心力衰竭。然而，与衰竭心脏进行性能量代谢死亡和收缩功能障碍相关的特定PGC-1靶基因和通路仍不清楚。这一建议旨在检验这样一个假设，即PGC-1下游过程的活性失调？那PGC-1呢？导致线粒体功能障碍，并导致导致心力衰竭的病理重塑。也有人提出，下调PGC-1靶点的子集，包括那些参与燃料偏好转变的靶点，可能在病理生理应激的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，结合无偏见的基因转录和定向的、基于质谱学的代谢物分析。目标1的目的将是确定心脏中相关的失调基因和改变的代谢物谱，可诱导的心脏特异的PGC-1？/？心力衰竭功能丧失小鼠模型。在目标2中，目标1中的数据集将与那些通过基因工程建立线粒体燃料燃烧错乱模型的小鼠的数据集进行比较，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，将对野生型小鼠的心脏进行基因组和代谢组谱分析：1)生理性(运动性)心肌肥厚；2)代偿性病理性心肌肥厚；3)失代偿性心肌肥厚(衰竭心脏)。来自AIMS 1-3的数据集的基于信息学的比较分析将被用来生成基因、代谢物和相应的代谢途径/过程的优先列表，这些基因、代谢物和相应的代谢途径/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错乱的候选签名，将在AIMS 4中得到进一步验证。该项目的长期目标是评估调节候选途径以维持心肌线粒体功能作为预防和治疗心力衰竭的新治疗方法的有效性。 (摘要结束)

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)