Probing the Cardiac PGC-1 Regulatory Cascade

探索心脏 PGC-1 监管级联

• 批准号: 8690130
• 负责人: DANIEL PATRICK KELLY
• 金额: $ 47.3万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690130
• 关键词: Acute; Adult; Biogenesis; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Chronic; Data Set; Development; Energy Metabolism; Energy Supply; Event; Funding; Gene Expression; Health; Heart; Heart Hypertrophy; Heart failure; Lead; Link; Metabolic; Mitochondria; Modeling; Molecular; Mus; Muscle Cells; Myocardial; Nuclear Receptors; Pathogenesis; Pathologic; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmacotherapy; Phenotype; Prevalence; Prevention; Process; Proteomics; Pump; Regulation; Regulator Genes; Role; Signal Transduction; Staging; Syndrome; Testing; Therapeutic; Transcription Coactivator; Wild Type Mouse; Work; estrogen-related receptor; heart metabolism; insight; loss of function; new therapeutic target; novel; novel strategies; postnatal; prenatal; pressure; prevent; public health relevance; respiratory; transcription factor

DESCRIPTION (provided by applicant): Despite recent advances in the prevention and treatment of cardiovascular disease, the prevalence of heart failure, a worldwide health threat, continues to grow. Current therapeutic strategies for heart failure are largely directed at disturbances in the neurohormonal axis rather than targeting the myocyte. Evidence is emerging that alterations in myocyte energy metabolism contributes to the pathogenesis of heart failure. Previous work linked to this RO1-funded project has shown that a gene regulatory cascade, under the influence of the transcriptional coactivators, PPAR3 transcriptional coactivator-11 and 2 (PGC-11 and PGC-12), controls the expression of genes involved in a wide array of mitochondrial energy transduction and ATP-generating processes in the cardiac myocyte. The results of our recent studies conducted in mice deficient for the PGC-1 coactivators have shown that the PGC-1 regulatory cascade is required for postnatal mitochondrial biogenic maturation. We have also found that the expression and activity of the PGC-1 coactivators are downregulated in pathologic forms of cardiac hypertrophy and in the failing heart. These findings have led to the central hypothesis of this renewal proposal that chronic deactivation of PGC-1 signaling in the adult heart contributes to the progressive pathologic metabolic and functional remodeling that leads to end-stage heart failure. To test this hypothesis we will: (1) conduct mitochondrial functional and proteomic studies in the hearts of adult mice in which the cardiac PGC-1 gene regulatory cascade has been deactivated; (2) define mitochondrial functional and proteomic derangements in hearts of wild-type mice subjected to pressure overload and ischemic insult and compare the results with the dataset generated in the PGC-1-deficient hearts in order to identify shared signatures; (3) explore the potential role of PGC-1 coactivators in the control of mitochondrial dynamics (fusion, fission, biogenesis); and (4) devise and implement proof-of-concept "rescue" studies in which PGC-1 coactivators or relevant downstream targets are reactivated in heart failure models in wild-type mice. In the long-term, we seek to identify and validate novel targets aimed at modulating cardiac metabolism as a novel approach to prevent or treat heart failure in its early stages. )

描述（由申请人提供）：尽管最近在心血管疾病的预防和治疗方面取得了进展，但作为全球健康威胁的心力衰竭的患病率仍在继续增长。目前心力衰竭的治疗策略主要是针对神经激素轴的干扰，而不是针对心肌细胞。有证据表明，心肌细胞能量代谢的改变与心力衰竭的发病机制有关。先前与ro1资助的项目相关的工作表明，在转录共激活因子PPAR3转录共激活因子-11和2 （PGC-11和PGC-12）的影响下，基因调控级联控制心肌细胞中参与广泛线粒体能量转导和atp生成过程的基因的表达。我们最近在缺乏PGC-1共激活因子的小鼠中进行的研究结果表明，PGC-1调控级联是出生后线粒体生物源成熟所必需的。我们还发现PGC-1共激活因子的表达和活性在心脏肥大和心力衰竭的病理形式中下调。这些发现导致了这一更新提议的中心假设，即成人心脏中PGC-1信号的慢性失活有助于进行性病理代谢和功能重塑，从而导致终末期心力衰竭。为了验证这一假设，我们将：(1)在心脏PGC-1基因调控级联失活的成年小鼠心脏中进行线粒体功能和蛋白质组学研究；(2)定义压力过载和缺血损伤下野生型小鼠心脏的线粒体功能和蛋白质组学紊乱，并将结果与pgc -1缺陷心脏产生的数据集进行比较，以确定共享特征；(3)探索PGC-1共激活因子在线粒体动力学（融合、裂变、生物发生）控制中的潜在作用；(4)设计并实施概念验证“拯救”研究，在野生型小鼠心力衰竭模型中重新激活PGC-1共激活因子或相关下游靶点。从长远来看，我们寻求确定和验证旨在调节心脏代谢的新靶点，作为预防或治疗早期心力衰竭的新方法。