Probing the Cardiac PGC-1 Regulatory Cascade

摘要 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了向成体程序的转变，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 确定参与心脏早期发育和形态发生的基因调节和信号事件， 有关出生后心脏发育成熟的机制尚不清楚。勾画 驱动心肌细胞成熟的回路与心脏病有关，因为在发育过程中 在心力衰竭的情况下，许多新陈代谢和收缩过程转变为不成熟或“胎儿”状态。此外，a 更好地了解推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人心肌细胞 包括概念验证治疗研究在内的系统。我们最近的研究表明，核受体 ERR和是pGC-1转录调控电路的中心效应器，是线粒体的关键驱动因素 在出生后心脏发育和成人心脏中的生物发生和成熟。最近，我们发现 错误不仅是线粒体成熟的调节者，也是出生后心脏发育所必需的。 发展。我们试图定义在出生后心脏的广泛计划中涉及的参与者和机制。 从PGC-1/ERR复合体开始成熟。这个项目的定义是为了测试新的假设，即 核受体Err和是前列腺素C-1诱导的转录调控的中心成分 循环，是更广泛的心脏成熟网络的关键组成部分。拟议中的实验 计划，得到过去两年现有资金的初步数据和试剂的支持 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 人体心脏组织图谱。使用ERR作为锚连接，我们将：1)定义蛋白质相互作用网络 转录调控因子和表观基因组调控因子与ERRS(err相互作用组)合作来协调 代谢性和非代谢性心肌细胞基因靶向表达；2)识别上游因素和信号 在心脏成熟过程中触发PGC-1/ERR通路的激活；以及3)决定该网络如何 在心力衰竭的发展过程中转变为胎儿状态，并评估其重新激活的可能性 改善临床前心力衰竭模型的病理性心脏重构。计划中的研究将导致 对胎儿心脏转化为成人心脏和意志的机制的重要新见解 提供深入的、临床前的、重新激活心肌细胞成熟的潜力的评估作为一种新的 治疗心力衰竭。

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.