Probing the Cardiac PGC-1 Regulatory Cascade

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，但心力衰竭这一世界性健康威胁的患病率仍在继续增长。目前心力衰竭的治疗策略主要针对神经激素轴的紊乱，而不是针对心肌细胞。越来越多的证据表明，心肌细胞能量代谢的改变有助于心力衰竭的发病。与这个由RO1资助的项目相关的以前的工作表明，在转录辅助激活因子PPAR3转录辅助激活因子-11和2(PGC-11和PGC-12)的影响下，基因调节级联反应控制着参与心肌细胞中广泛的线粒体能量转导和ATP生成过程的基因的表达。我们最近在缺乏PGC-1共激活子的小鼠身上进行的研究结果表明，PGC-1调节级联是出生后线粒体生物起源成熟所必需的。我们还发现，PGC-1共激活子的表达和活性在心肌肥厚的病理形式和衰竭的心脏中下调。这些发现导致了这一更新建议的中心假设，即成人心脏中PGC-1信号的慢性失活导致了导致终末期心力衰竭的进行性病理代谢和功能重塑。为了验证这一假说，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)定义压力超负荷和缺血性损伤下野生型小鼠心脏的线粒体功能和蛋白质组排列，并将结果与PGC-1缺陷心脏产生的数据集进行比较，以确定共同的特征；(3)探索PGC-1辅活化子在线粒体动力学(融合、裂变、生物发生)控制中的潜在作用；以及(4)设计和实施概念验证“救援”研究，在野生型小鼠的心力衰竭模型中，PGC-1共激活子或相关的下游靶点重新激活。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。)

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. )