Function and regulation of copper in mammalian tissue differentiation

铜在哺乳动物组织分化中的功能和调节

• 批准号: 10661077
• 负责人: Katherine Elizabeth Vest
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661077
• 关键词: ATP phosphohydrolase; Cell Differentiation process; Cells; Copper; Data; Defect; Deficiency Diseases; Development; Disease; Equilibrium; Excision; Gene Expression; Genetic; Golgi Apparatus; Growth Factor; Homeostasis; Impairment; In Vitro; Iron; Knowledge; Menkes Kinky Hair Syndrome; Metabolic Pathway; Muscle Fibers; Muscle hypotonia; Nerve Degeneration; Neurons; Normal tissue morphology; Oxidative Phosphorylation; Post-Transcriptional Regulation; Process; RNA; Reactive Oxygen Species; Regulation; Regulatory Pathway; Research; Respiration; Role; Series; Signal Pathway; Signal Transduction; Tissue Differentiation; Tissues; Trace Elements Nutrition; Work; cofactor; developmental disease; disease-causing mutation; human disease; in vivo; postnatal; posttranscriptional; prevent; programs; skeletal muscle differentiation; therapy development

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.

项目摘要/摘要 哺乳动物组织的发育需要一系列严格调节和动态波动 在代谢途径中，生长因子信号传导，基因表达和辅助因子的可用性。一个 重要的辅助因子是铜（Cu），这是一种必不可少但有毒的痕量营养素，是氧化所必需的 磷酸化，反应性氧的去除，铁稳态和促生物存在 信号通路。 CU对于正常组织的发展很重要，我们和其他人有 表明Cu是分化骨骼肌和神经元细胞所必需的。这需要 在CU缺乏的情况下，严重的产后发育障碍强调了CU 包括深度低调和神经变性。 Menkes是致命的遗传CU缺乏症 由ATP7A突变引起的疾病，该突变编码转运ATPase的反式高尔基铜。 关于组织分化过程中关键CU目标的几个开放性问题以及如何 受调节的基因表达有助于将CU分布确定到这些靶标。这些 问题在CU处理方面造成了差距，这将疗法的发展限制为 治疗包括Menkes在内的CU疾病。我们的初步数据表明ATP7A是必需的 骨骼肌细胞分化以及CU和ATP7A可能有助于受调节的抑制作用 防止分化的TGF-信号通路。我们还发现 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要了解的项目 首先专注于功能和 ATP7A的调节。第一个项目将研究CU和ATP7A在调节TGF-中的作用 信号传导以促进体外和体内分化。第二个将着重于发现 ATP7A RNA转录后调节的机制及其如何控制ATP7A 表达。这些项目将确定由CU和New规范的新信号通路 Cu调节的机制。这项工作将开放通过调节CU可用性的可能性 针对转录后调节途径，并提高控制TGF-的可能性 通过操纵Cu可用性来处理与CU相关和发育疾病的信号传导。