Function and regulation of copper in mammalian tissue differentiation

项目概要/摘要 哺乳动物组织发育需要一系列严格调控的动态波动 代谢途径、生长因子信号传导、基因表达和辅因子可用性。安 重要的辅助因子是铜 (Cu)，它是氧化所需的必需但有毒的微量营养素 磷酸化、活性氧的去除、铁稳态和促生存 信号通路。铜对于正常组织发育很重要，我们和其他人已经发现 研究表明，铜是骨骼肌和神经元细胞分化所必需的。这需要 缺铜会导致严重的产后发育障碍，这凸显了铜的重要性 包括严重的肌张力减退和神经变性。门克斯是一种致命的遗传性铜缺乏症 由 ATP7A 突变引起的疾病，ATP7A 编码反式高尔基体 Cu 转运 ATP 酶。 关于组织分化过程中的关键铜靶标以及如何 受调控的基因表达有助于将铜优先分配到这些目标。这些 问题造成了铜处理知识的空白，限制了治疗方法的开发 治疗铜疾病，包括门克斯病。我们的初步数据表明 ATP7A 是 骨骼肌细胞分化，Cu 和 ATP7A 可能有助于调节抑制 阻碍分化的 TGF-β 信号通路。我们还发现，后 Atp7a RNA 的转录调控有助于分化依赖性调节 ATP7A 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和 ATP7A 的调节。第一个项目将研究 Cu 和 ATP7A 在调节 TGF-β 中的作用 促进体外和体内分化的信号传导。第二个重点是揭示 Atp7a RNA 转录后调控机制及其如何控制 ATP7A 表达。这些项目将确定铜调控的新信号通路和新的信号通路 Cu 调节机制。这项工作将开启通过以下方式调节铜可用性的可能性 靶向转录后调控途径并提高控制 TGF- 的可能性 通过操纵铜的可用性来治疗铜相关疾病和发育疾病。

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.