Function and regulation of copper in mammalian tissue differentiation

项目摘要/摘要 哺乳动物组织的发育需要一系列严格调控的动态波动 在代谢途径中，生长因子信号、基因表达和辅因子可利用性。一个 重要的辅因是铜，这是氧化所需的一种基本但有毒的微量营养物质 磷酸化、清除活性氧、铁稳态和促生存 信号通路。铜对正常的组织发育很重要，我们和其他人有 表明铜是骨骼肌和神经细胞分化所必需的。这一需求 铜缺乏症患者的严重出生后发育障碍是铜的突出特征 包括严重的低眼压和神经变性。孟克斯是一种致命的遗传性铜缺乏 由ATP7A突变引起的疾病，ATP7A编码反式高尔基铜转运ATPase。 关于组织分化过程中关键的铜靶点以及如何 受调控的基因表达有助于铜优先分配到这些靶点。这些 问题造成了铜处理知识的空白，限制了治疗方法的发展 治疗包括门可氏症在内的铜病。我们的初步数据表明，ATP7A是 骨骼肌细胞分化及铜和ATP7A可能参与调节抑制 抑制分化的转化生长因子-信号通路。我们还发现，POST- ATP7A RNA的转录调控有助于分化相关的调节 ATP7A的表达。拟议的研究计划包括两个需要了解的项目 在骨骼肌分化过程中铜的优先顺序首先关注功能和 ATP7A的调控。第一个项目将研究铜和ATP7A在调节转化生长因子-中的作用 在体外和体内促进分化的信号。第二个将专注于揭开 ATP7A RNA转录后调控机制及其对ATP7A的调控 表情。这些项目将确定由铜和新的 铜的调节机制。这项工作将开启通过以下方式调节铜有效性的可能性 靶向转录后调控通路，提高控制转化生长因子-的可能性 通过控制铜的有效性来治疗铜相关和发育性疾病。

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.