Function and regulation of copper in mammalian tissue differentiation

项目总结/摘要 哺乳动物的组织发育需要一系列严格调控的动态波动 在代谢途径、生长因子信号传导、基因表达和辅因子可用性方面。一个 重要的辅因子是铜（Cu），一种必需但有毒的微量营养素， 磷酸化，清除活性氧，铁稳态和促生存 信号通路铜对正常组织发育很重要，我们和其他人已经 表明铜是骨骼肌和神经元细胞分化所必需的。这种需要 铜是突出的严重产后发育障碍的情况下，铜缺乏症 包括严重的张力减退和神经退化Menkes是一种致命的遗传性铜缺乏症 由ATP 7A突变引起的疾病，ATP 7A编码trans-Golgi Cu转运ATP酶。 关于组织分化过程中关键的铜靶点以及如何作用， 受调节的基因表达有助于优先Cu分布到那些靶标。这些 这些问题造成了铜处理知识的空白，限制了治疗的发展， 治疗铜病，包括Menkes。我们的初步数据表明，ATP 7A是必需的， 骨骼肌细胞分化和铜和ATP 7A可能有助于调节抑制 TGF-β信号通路阻止分化。我们还发现后- Atp 7a RNA的转录调控有助于细胞分化依赖性的调节， ATP 7A表达。拟议的研究计划包括两个项目，以了解 骨骼肌分化过程中铜的优先顺序，首先关注功能， ATP 7A的作用第一个项目将研究Cu和ATP 7A在调节TGF-β 1中的作用。 信号传导以促进体外和体内分化。第二个将侧重于揭示 Atp 7a RNA的转录后调控机制及其如何控制Atp 7A 表情这些项目将确定由Cu调节的新信号通路， 铜调控机制。这项工作将打开调节铜的可用性的可能性， 靶向转录后调节途径，提高控制TGF-β 1的可能性， 通过操纵Cu的可用性来治疗Cu相关的和发育的疾病。

PROJECT SUMMARY/ABSTRACT Mammalian tissue development requires a series of tightly regulated and dynamic fluctuations in metabolic pathways, growth factor signaling, gene expression, and cofactor availability. An important cofactor is copper (Cu), an essential but toxic trace nutrient that is required for oxidative phosphorylation, removal of reactive oxygen species, iron homeostasis, and pro-survival signaling pathways. Cu is important for normal tissue development, and we and others have shown that Cu is required for differentiation of skeletal muscle and neuronal cells. This need for Cu is highlighted by the severe postnatal developmental impairment in cases of Cu deficiency including profound hypotonia and neurodegeneration. Menkes is a fatal genetic Cu deficiency disease caused by mutations in ATP7A, which encodes a trans-Golgi Cu transporting ATPase. Several open questions remain about the critical Cu targets during tissue differentiation and how regulated gene expression contributes to prioritized Cu distribution to those targets. These questions create a gap in knowledge of Cu handling that limit the development of therapies to treat Cu diseases including Menkes. Our preliminary data indicate that ATP7A is required for skeletal muscle cell differentiation and that Cu and ATP7A may contribute to regulated inhibition of TGF- signaling pathways that prevent differentiation. We also discovered that post- transcriptional regulation of the Atp7a RNA contributes to differentiation-dependent tuning of ATP7A expression. The proposed research program includes two projects to understand prioritization of Cu during skeletal muscle differentiation by first focusing on function and regulation of ATP7A. The first project will study the role of Cu and ATP7A in modulating TGF- signaling to promote differentiation in vitro and in vivo. The second will focus on uncovering the mechanisms of post-transcriptional regulation of Atp7a RNA and how they control ATP7A expression. These projects will identify new signaling pathways regulated by Cu and new mechanisms of Cu regulation. This work will open the possibility of modulating Cu availability by targeting post-transcriptional regulatory pathways and raise the possibility of controlling TGF- signaling by manipulating Cu availability to treat Cu-related and developmental disease.