COPPER HOMEOSTASIS IN MAMMALS

微量金属铜（Cu）是生命所必需的关键元素， 多种酶的辅因子，在这些过程中发挥关键作用， 如呼吸、结缔组织成熟、铁动员、氧化 应激保护和神经肽加工。哺乳动物无法 获得足够的铜与发育异常的 中枢神经系统、贫血、血管生成缺陷和多种其他疾病 生长和发育的缺陷。虽然细胞成分参与铜 在低等真核生物中已经确定了摄取，但对摄取的影响知之甚少。 介导铜获得的蛋白质的身份，也不是他们的机制， 哺乳动物的行为或调节。人和小鼠Ctrl互补DNA具有 基于它们抑制生长和生化缺陷的能力而被分离 与面包酵母细胞相关， 运输虽然哺乳动物Ctrl的结构，其组织特异性 表达及其在酵母和培养物中刺激铜获得的能力 人类细胞相容性与高亲和力铜转运的作用， Ctrl在哺乳动物中的生理作用及其作用机制， 规则不明。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运输中的生理作用将是 通过创建和分析缺乏功能性Ctrl的小鼠来确定 基因第二，组织特异性表达、发育调控和 将表征小鼠Ctrl蛋白的定位。三是 Ctrl促进Cu跨细胞转运的机制 膜以及如何调节这一过程可能作为饮食铜的功能 需求将被确定。第四，哺乳动物Ctr2 蛋白质功能，与Ctrl一致，以促进并可能调节Cu 收购将得到澄清。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得铜以及如何获得铜的重要信息 不适当的铜获取导致病理生理状态， 其潜在的基础，铜依赖的生物化学过程中的缺陷。

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.