Probing the Cardiac PGC-1 Regulatory Cascade

探索心脏 PGC-1 监管级联

• 批准号: 10579239
• 负责人: DANIEL PATRICK KELLY
• 金额: $ 65.03万
• 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/10579239
• 关键词: Adult; Area; Automobile Driving; Biogenesis; Birth; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cells; Complex; Coupled; Data; Development; 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; Nuclear Receptors; Pathologic; Pathway interactions; Performance; Perinatal; Perinatal mortality demographics; Pluripotent Stem Cells; Process; Proteins; Proteomics; Reagent; 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; insight; mouse model; novel; novel therapeutic intervention; novel therapeutics; postnatal; pre-clinical; prevent; programs; 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.

总结 在胎儿到成人的过渡期间，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包括线粒体能力的成人程序的转化， 燃料利用途径和收缩机制。鉴于在以下方面取得了相当大的进展， 定义了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， 对出生后心脏发育成熟的机制知之甚少。划定 驱动心肌细胞成熟的回路与心脏病有关， 在心力衰竭时，许多代谢和收缩过程转变为不成熟或“胎儿”状态。另外还有按 更好地理解驱动心肌细胞成熟的机制将为 使人诱导多能干细胞在实验中完全成熟为成体心肌细胞 包括概念验证治疗研究在内的系统。我们最近的研究表明， PGC-1转录调控回路的中心效应子ERR β和ERK β是线粒体DNA转录调控的关键驱动因子。 出生后心脏发育期间以及成年心脏中的生物发生和成熟。最近，我们发现 ERRs不仅是线粒体成熟的调节因子，也是出生后心脏发育所必需的。 发展我们试图定义参与出生后心脏病广泛程序的参与者和机制， 通过以PGC-1/ERR复合物开始成熟。这个项目被定义为测试新的假设， 核受体ERR β和ERR β是PGC-1诱导的转录调控的中心成分， 循环，作为更广泛的心脏成熟网络的关键组成部分。拟议的实验 该计划得到了现有资金过去两年开发的初步数据和试剂的支持 期间，将采用最先进的蛋白质组学，功能基因组学，小鼠体内研究， 人类心脏组织分析使用ERR作为锚联系，我们将：1）定义蛋白质相互作用网络 转录和表观基因组调节因子与ERR（ERR相互作用组）合作， 代谢和非代谢心肌细胞基因靶向表达; 2）识别上游因子和信号 在心脏成熟过程中触发PGC-1/ERR回路激活;以及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可能性， 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 重要的新见解的机制，使胎儿的心脏转化为成人的心脏，并将 提供了对重新激活心肌细胞成熟作为一种新的治疗方法的潜力的深入的临床前评估。 治疗心力衰竭的药物