COPPER HOMEOSTASIS IN MAMMALS

哺乳动物中的铜稳态

• 批准号: 6256434
• 负责人: DENNIS J. THIELE
• 金额: $ 20.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6256434
• 关键词: amine oxidoreductase; copper; cytochrome oxidase; developmental genetics; enzyme activity; ferroxidase; gene induction /repression; gene targeting; genetically modified animals; homeostasis; laboratory mouse; membrane transport proteins; metal metabolism; protein structure function; superoxide dismutase

The trace metal copper (Cu) is essential for life as a critical co-factor for a wide variety of enzymes that play key roles in processes such as respiration, connective tissue maturation, iron mobilization, oxidative stress protection and neuropeptide processing. The inability of mammals to acquire sufficient Cu is associated with developmental abnormalities of the central nervous system, anemia, defects in angiogenesis and a variety of other defects in growth and development. Although cellular components involved in Cu uptake have been identified in lower eukaryotes, little is known about the identity of proteins that mediate Cu acquisition, nor their mechanisms of action or regulation in mammals. Human and mouse Ctrl complementary DNAs have been isolated based on their ability to suppress growth and biochemical defects associated with baker's yeast cells that are defective in high affinity Cu transport. Although the structure of mammalian Ctrl, its tissue-specific expression and its ability to stimulate Cu acquisition in yeast and cultured human cells are compatible with a role in high affinity Cu transport, the physiological role of Ctrl in mammals, and its mechanisms of action and regulation are unknown. This proposal describes avenues of investigation with the goal of understanding the role and mechanism of action of Ctrl in mammalian Cu acquisition. First, the physiological role of Ctrl in Cu transport will be determined through the creation and analysis of mice lacking a functional Ctrl gene. Second, the tissue-specific expression, developmental regulation and localization of the mouse Ctrl protein will be characterized. Third, the mechanisms by which Ctrl facilitates the transport of Cu across cellular membranes and how this process may be regulated as a function of dietary Cu need will be ascertained. Fourth, the mechanisms by which mammalian Ctr2 protein functions, in concert with Ctrl, to facilitate and perhaps modulate Cu acquisition will be elucidated. These investigations will provide fundamentally important information on how mammals acquire Cu from nutrients and how inappropriate Cu acquisition leads to pathophysiological states that have, as their underlying basis, defects in Cu-dependent biochemical processes.

微量金属铜 (Cu) 作为生命的关键物质而至关重要 多种酶的辅助因子，这些酶在诸如 如呼吸、结缔组织成熟、铁动员、氧化 应激保护和神经肽加工。哺乳动物没有能力 获得足够的铜与发育异常有关 中枢神经系统、贫血、血管生成缺陷和各种其他 生长和发育的缺陷。尽管细胞成分涉及铜 已在低等真核生物中发现了吸收，但人们对其知之甚少 介导铜获取的蛋白质的身份及其机制 在哺乳动物中的作用或调节。人类和小鼠 Ctrl 互补 DNA 基于其抑制生长和生化缺陷的能力而被分离 与高亲和力铜缺陷的面包酵母细胞有关 运输。尽管哺乳动物 Ctrl 的结构，其组织特异性 表达及其刺激酵母和培养物中铜获取的能力 人类细胞与高亲和力铜转运的作用相容， Ctrl在哺乳动物中的生理作用及其作用机制和 监管未知。该提案描述了调查途径 目的是了解 Ctrl 在哺乳动物中的作用和作用机制 铜收购。首先，Ctrl 在 Cu 转运中的生理作用是 通过创建和分析缺乏功能性 Ctrl 的小鼠来确定 基因。二、组织特异性表达、发育调控和 将表征小鼠 Ctrl 蛋白的定位。第三， Ctrl 促进铜跨细胞转运的机制 膜以及如何根据膳食铜来调节这一过程 将确定需要。四、哺乳动物Ctr2的机制 蛋白质功能，与 Ctrl 配合，促进并可能调节 Cu 收购将得到阐明。这些调查将从根本上提供 关于哺乳动物如何从营养物质中获取铜以及如何 铜获取不当会导致病理生理状态，如 它们的根本基础是铜依赖性生化过程的缺陷。