Probing the Cardiac PGC-1 Regulatory Cascade

探索心脏 PGC-1 监管级联

• 批准号: 8548543
• 负责人: DANIEL PATRICK KELLY
• 金额: $ 3.9万
• 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/8548543
• 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. ) PUBLIC HEALTH RELEVANCE: Heart failure is a growing worldwide health threat. This project seeks to understand how changes in the metabolism of the heart contribute to the development of heart failure. This work should identify new approaches to treat heart failure by boosting its energy supply.

描述（由申请人提供）：尽管最近在预防和治疗心血管疾病方面取得了进展，但作为全球健康威胁的心力衰竭的患病率仍在持续增长。目前心力衰竭的治疗策略主要针对神经激素轴的紊乱，而不是针对肌细胞。越来越多的证据表明，心肌细胞能量代谢的改变导致心力衰竭的发病机制。之前与这个 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，基因调控级联控制着心肌细胞中参与多种线粒体能量转导和 ATP 生成过程的基因表达。我们最近在缺乏 PGC-1 共激活剂的小鼠中进行的研究结果表明，PGC-1 调节级联是出生后线粒体生物成熟所必需的。我们还发现，PGC-1 共激活剂的表达和活性在心脏肥大和心脏衰竭的病理形式中下调。这些发现引发了这一更新提案的中心假设，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。为了检验这一假设，我们将：（1）在心脏 PGC-1 基因调控级联已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) 确定承受压力超负荷和缺血性损伤的野生型小鼠心脏中的线粒体功能和蛋白质组紊乱，并将结果与​​ PGC-1 缺陷心脏中生成的数据集进行比较，以确定共同的特征； （3）探索PGC-1共激活剂在控制线粒体动力学（融合、裂变、生物发生）中的潜在作用； (4) 设计并实施概念验证“救援”研究，其中 PGC-1 共激活剂或相关下游靶标在野生型小鼠心力衰竭模型中被重新激活。从长远来看，我们寻求识别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。 ） 公共卫生相关性：心力衰竭是全球日益严重的健康威胁。该项目旨在了解心脏新陈代谢的变化如何导致心力衰竭的发展。这项工作应该找到通过增加能量供应来治疗心力衰竭的新方法。