Copper Homeostasis in Mammals

描述（申请人提供）：铜（Cu）在生物化学反应中起着关键的催化和调节作用，对正常生长、发育和健康至关重要。门克斯病和威尔逊病是两种严重的人类铜代谢遗传性疾病，分别导致儿童死亡和肝脏和神经功能障碍。不适当的铜平衡与脊髓神经病变、朊病毒病、阿尔茨海默病、心血管疾病和癌症有关。因此，了解细胞控制铜的获取、分布和利用的机制是至关重要的。虽然对Cu输入、细胞内分布和外排机制的识别和功能已经开始了解，但我们对Ctr2蛋白的生理作用、Cu输入的调节以及生物体如何建立全球Cu稳态知之甚少。在本应用中概述了三个具体目标，这些目标通过它们将破译哺乳动物铜转运机制的作用机制及其在细胞和系统水平上的调节的信息而相互关联。在第一个具体目标中，将通过小鼠Ctr2敲除突变体的分析、培养细胞的生化和细胞生物学实验以及Ctr2突变蛋白的分析来确定哺乳动物Ctr2蛋白在Cu获取中的生理作用。在第二个特定目标中，Ctr1 Cu进口蛋白和Ctr2蛋白的调控将通过分析它们在细胞培养中的翻译后调控来破译。在第三个特定目标中，实验概述了识别一种新的血液传播信号，该信号允许外周器官（如心脏）与铜获取和储存器官之间的器官间通信。综上所述，这些研究将破译铜获取机制的关键功能角色和细胞和系统调节机制，其功能对正常生长、发育和人类健康至关重要。

DESCRIPTION (provided by applicant): Copper (Cu) plays key catalytic and regulatory functions for biochemical reactions that are critical to normal growth, development and health. Menkes disease and Wilson's disease are two severe human genetic disorders of Cu metabolism that result in childhood mortality and hepatic and neurological dysfunction, respectively. Inappropriate copper balance is linked to myeloneuropathy, prion disease, Alzheimer's and cardiovascular disease and cancer. Consequently, it is critical to understand the mechanisms by which cells control the acquisition, distribution and utilization of Cu. While the identify and functions of the Cu import, intracellular distribution and efflux machinery are beginning to be understood, we know very little about the physiological role of the Ctr2 protein, the regulation of Cu import and how organisms establish global Cu homeostasis. Three specific aims are outlined in this application, which are inter- related by the information they will decipher on the mechanisms of action of the mammalian Cu transport machinery and its regulation at the cellular and systemic level. In the first specific aim the physiological role of the mammalian Ctr2 protein in Cu acquisition will be ascertained through the analysis of mouse Ctr2 knock out mutants, through biochemical and cell biological experiments in cultured cells and through the analysis of Ctr2 mutant proteins. In the second specific aim the regulation of the Ctr1 Cu importer and the Ctr2 protein will be deciphered through an analysis of their post- translational regulation in cell culture. In the third specific aim experiments are outlined to identify a novel blood-borne signal that allows inter-organ communication between peripheral organs such as the heart and the copper acquisition and storage organs. Taken together, these investigations will decipher key functional roles and cellular and systemic regulatory mechanisms for the Cu acquisition machinery, the function of which is essential for normal growth, development and human health. PUBLIC HEALTH RELEVANCE: Copper is an essential element for human health and the inability to properly regulate copper balance is associated with lethal childhood disease, liver and neurological disease, Alzheimer's disease, cardiovascular disease and cancer. The research outlined in this application is designed to understand how mammals properly acquire copper and how copper acquisition is regulated. These studies may identify pathways and potential therapeutic avenues that are important in human diseases of copper balance.