Probing the Cardiac PGC-1 Regulatory Cascade

探索心脏 PGC-1 监管级联

• 批准号: 10378059
• 负责人: DANIEL PATRICK KELLY
• 金额: $ 65.36万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378059
• 关键词: Adult; Area; Automobile Driving; Biogenesis; Birth; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiac development; Cells; Complex; Coupled; Data; Development; ERR1 protein; Estrogen Nuclear Receptor; Event; Fetal Development; Fetal Heart; Fibrosis; Funding; Gene Targeting; Genetic Transcription; Genomics; Goals; Heart; Heart Diseases; Heart failure; Histones; Human; Hypertrophy; Immunoprecipitation; Investigation; Ion Transport; Knock-out; Mass Spectrum Analysis; Metabolic; Mitochondria; Modeling; Morphogenesis; Mus; Pathologic; Pathway interactions; Performance; Perinatal; Perinatal mortality demographics; Peroxisome Proliferator-Activated Receptors; Process; Proteins; Proteomics; Reagent; Receptor Signaling; Regulator Genes; Role; Signal Transduction; Structural Genes; System; Testing; Therapeutic Studies; Tissues; Work; cardiogenesis; coronary fibrosis; epigenomics; estrogen-related receptor; fetal; functional genomics; in vivo; induced pluripotent stem cell; insight; mouse model; novel; novel therapeutic intervention; novel therapeutics; postnatal; pre-clinical; pre-clinical assessment; prevent; programs; receptor; stressor; transcription regulatory network; validation studies; virtual; whole genome

SUMMARY During the fetal to adult transition, the heart undergoes dramatic developmental maturation. Following birth, many cardiac myocyte processes undergo transformation to adult programs including mitochondrial capacity, fuel utilization pathways, and the contractile machinery. Whereas, considerable progress has been made in defining the gene regulatory and signaling events involved in early cardiac development and morphogenesis, the mechanisms involved in postnatal cardiac developmental maturation are poorly understood. Delineation of the circuitry driving cardiac myocyte maturation is relevant to heart disease given that during the development of heart failure, many metabolic and contractile processes shift to an immature or “fetal” state. In addition, a better understanding of the mechanisms driving cardiac myocyte maturation will provide new strategies for enabling full maturation of human induced-pluripotent stem cells into adult cardiac myocytes in experimental systems including proof-of-concept therapeutic studies. Our recent work has shown that the nuclear receptors ERR and, central effectors of the PGC-1 transcriptional regulatory circuit, are key drivers of mitochondrial biogenesis and maturation during postnatal cardiac development, and in the adult heart. Very recently, we found that the ERRs are not only regulators of mitochondrial maturation, but are also necessary for postnatal cardiac development. We seek to define the players and mechanisms involved in the broad program of postnatal cardiac maturation by starting with the PGC-1/ERR complex. This project is defined to test the novel hypothesis that the nuclear receptors ERR and, central components of the PGC-1-induced transcriptional regulatory circuit, function as key components of a broader cardiac maturation network. The proposed experimental plan, buttressed by preliminary data and reagents developed over the past two years of the current funding period, will employ a combination of state-of-the-art proteomics, functional genomics, in vivo studies in mice, and human heart tissue profiling. Using the ERR as an anchor nexus we will: 1) define the protein interaction network of transcriptional and epigenomic regulators that cooperate with the ERRs (ERR interactome) to orchestrate metabolic and non-metabolic cardiac myocyte gene target expression; 2) identify upstream factors and signals that trigger activation of the PGC-1/ERR circuitry during cardiac maturation; and 3) determine how this network shifts toward the fetal state during development of heart failure, and assess the potential of its re-activation to ameliorate pathological cardiac remodeling in pre-clinical heart failure models. The planned studies will lead to important new insights into the mechanisms whereby the fetal heart transforms into the adult heart and will provide in-depth, pre-clinical, assessment of the potential of re-activating cardiac myocyte maturation as a novel therapeutic for heart failure.

概括 在胎儿到成人的过渡过程中，心脏经历了戏剧性的发育成熟。出生后， 许多心肌细胞过程经历向成人程序的转变，包括线粒体能力， 燃料利用途径和收缩机械。鉴于在以下方面已经取得了相当大的进展 定义参与早期心脏发育和形态发生的基因调控和信号传导事件， 人们对出生后心脏发育成熟的机制知之甚少。划定 鉴于在发育过程中，驱动心肌细胞成熟的电路与心脏病相关 心力衰竭时，许多代谢和收缩过程会转变为不成熟或“胎儿”状态。此外，还有一个 更好地了解驱动心肌细胞成熟的机制将为心肌细胞成熟提供新的策略 在实验中使人类诱导多能干细胞完全成熟为成体心肌细胞 系统，包括概念验证治疗研究。我们最近的工作表明，核受体 ERR 和  是 PGC-1 转录调节回路的中心效应器，是线粒体的关键驱动因素。 出生后心脏发育期间以及成人心脏中的生物发生和成熟。就在最近，我们发现 ERR 不仅是线粒体成熟的调节因子，而且对于出生后心脏功能也是必需的 发展。我们寻求定义参与产后心脏病广泛计划的参与者和机制 从 PGC-1/ERR 复合体开始成熟。该项目的定义是为了测试以下新假设： 核受体 ERRα 和 β，PGC-1 诱导的转录调节的核心成分 电路，作为更广泛的心脏成熟网络的关键组成部分。拟议的实验 计划，得到了过去两年当前资金中开发的初步数据和试剂的支持 在此期间，将结合最先进的蛋白质组学、功能基因组学、小鼠体内研究以及 人类心脏组织分析。使用 ERR 作为锚链接，我们将：1) 定义蛋白质相互作用网络 与 ERR（ERR 相互作用组）合作协调的转录和表观基因组调节因子 代谢和非代谢心肌细胞基因靶标表达； 2) 识别上游因素和信号 在心脏成熟过程中触发 PGC-1/ERR 电路的激活； 3）确定该网络如何 在心力衰竭发展过程中向胎儿状态转变，并评估其重新激活的潜力 改善临床前心力衰竭模型中的病理性心脏重塑。计划中的研究将导致 关于胎儿心脏转变为成人心脏和意志的机制的重要新见解 对重新激活心肌细胞成熟作为一种新型药物的潜力提供深入的临床前评估 治疗心力衰竭。