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

• 批准号: 8063188
• 负责人: DANIEL PATRICK KELLY
• 金额: $ 72.76万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 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/8063188
• 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

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）： 尽管在过去几十年中，心血管疾病的治疗方面取得了重大进展，但治疗方法可防止导致心力衰竭的病理心肌重塑过程，这是一种全球健康威胁。有证据表明线粒体功能障碍有助于心力衰竭的发病机理。我们已经证明了转录共激活因子PPAR？转录共激活因子-1Alpha和beta（PGC-1？和PGC-1？）是正常的围产期线粒体生物发生和心脏中呼吸功能所必需的。 PGC-1的表达和活性？其几种转录因子靶标（PPAR？，ERR？），心脏肥大的病理形式和心脏失败的病理形式减少。最近的发现表明，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。但是，与渐进式能量代谢的衰减和收缩功能障碍相关的特定PGC-1靶基因和途径在失败的心脏中仍然未知。该建议旨在检验以下假设：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，在病理生理压力的背景下，PGC-1靶标的下调（包括参与燃料偏好转移的靶标的）可能具有保护性。为了解决这个问题，我们组装了一个多学科团队，使用了系统方法，结合了无偏基因转录和靶向的基于质谱的代谢物分析。目标1的目的是确定相关的失调基因并改变了诱导性，心脏特异性的PGC-1？/？/？功能丧失的心力衰竭小鼠模型。在AIM 2中，将将AIM 1中的数据集与对线粒体燃料燃烧中的模型扰动的小鼠的生成的数据进行比较，包括线粒体FA和葡萄糖氧化中的选择性块，但心脏功能正常。在AIM 3中，将使用野生型小鼠的心脏进行基因组和代谢组分析，其中：1）生理（运动诱导的）心脏肥大； 2）补偿病理心脏肥大； 3）心脏肥大（心脏衰竭）。来自目标1-3的数据集的基于信息的比较分析将用于生成优先的基因，代谢产物和相应的代谢途径/过程，这些途径/过程将作为线粒体危险的候选签名，与病理心脏代谢和功能性重塑的发展相关，以进一步验证该模态，以进一步验证该模态，以实现这一效果。维持心脏线粒体功能的候选途径是一种预防和治疗心力衰竭的新治疗方法。 （抽象的结尾）