COPPER HOMEOSTASIS IN MAMMALS

微量金属铜(铜)是生命中必不可少的关键物质 多种酶的辅因子，这些酶在过程中起关键作用 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 获得足够的铜与儿童发育异常有关 中枢神经系统、贫血、血管生成缺陷和其他各种疾病 生长发育方面的缺陷。尽管与铜有关的细胞成分 已经在低等真核生物中发现了摄取，对这种摄取知之甚少 介导铜摄取的蛋白质的特性及其作用机制 哺乳动物的行为或调节。人和小鼠的Ctrl互补DNA 根据它们抑制生长和生化缺陷的能力而被分离出来 与高亲和力铜缺陷的面包酵母细胞有关 运输。虽然哺乳动物Ctrl的结构，其组织特异性 酵母和培养物中铜的表达及其对铜吸收的刺激作用 人类细胞在高亲和力铜运输中的作用是相容的 Ctrl在哺乳动物中的生理作用及其作用机制 监管是未知的。这份提案描述了调查的途径 了解Ctrl在哺乳动物中的作用和作用机制 CU收购。首先，Ctrl在铜运输中的生理作用将是 通过建立和分析缺乏功能控制的小鼠来确定 吉恩。第二，组织特异性表达、发育调节和 将对小鼠Ctrl蛋白的定位进行表征。第三， Ctrl促进铜跨细胞转运的机制 膜以及这一过程如何作为日粮铜的函数来调节 需求将被确定。第四，哺乳动物Ctr2的机制 与Ctrl协同作用的蛋白质功能，促进并可能调节铜 收购将被阐明。这些调查将从根本上提供 关于哺乳动物如何从营养中获取铜以及如何获得铜的重要信息 不适当的铜摄取会导致AS的病理生理状态 它们的根本基础是依赖铜的生化过程中的缺陷。

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.