Copper Homeostasis in Mammals

哺乳动物的铜稳态

• 批准号: 8300126
• 负责人: Dennis J Thiele
• 金额: $ 33.71万
• 依托单位: DUKE UNIVERSITY
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300126
• 关键词: Affinity; Alzheimer' s Disease; Biochemical; Biochemical Reaction; Biological; Biological Availability; Blood; Blood Circulation; Cardiac; Cardiovascular Diseases; Cell Culture Techniques; Cells; Cellular biology; Childhood; Communication; Copper; Cultured Cells; Data; Defect; Disease; Elements; Equilibrium; Genes; Growth and Development function; Health; Heart; Hepatic; Hepatolenticular Degeneration; Hereditary Disease; Homeostasis; Hormones; Human; Human Genetics; Investigation; Knock-out; Knockout Mice; Laboratories; Link; Liver; Liver diseases; Maintenance; Malignant Neoplasms; Mammals; Menkes Kinky Hair Syndrome; Metabolism; Metals; Mus; Nature; Neurologic Dysfunctions; Organ; Organism; Oxidation-Reduction; Pathway interactions; Peripheral; Physiological; Pinocytosis; Play; Post-Translational Regulation; Prion Diseases; Proteins; RNA Interference; Regulation; Reporting; Research; Role; Serum; Signal Transduction; Signaling Protein; Site; Testing; Therapeutic; Tissues; Yeasts; base; design; efflux pump; human disease; intestinal epithelium; mortality; mutant; nervous system disorder; novel; prevent; research study; small molecule; uptake

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.

描述（由申请人提供）：铜（Cu）在对正常生长、发育和健康至关重要的生化反应中起着关键的催化和调节作用。Menkes病和Wilson病是两种严重的人类铜代谢遗传性疾病，分别导致儿童死亡以及肝脏和神经功能障碍。不适当的铜平衡与脊髓神经病、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、分布和利用的机制至关重要。虽然铜的输入，细胞内分布和外排机制的识别和功能开始被理解，我们知道很少的Ctr2蛋白的生理作用，铜输入的调节和生物体如何建立全球铜稳态。在本申请中概述了三个具体目标，它们通过它们将在哺乳动物Cu转运机制的作用机制及其在细胞和系统水平上的调节上破译的信息而相互关联。在第一个具体目标中，哺乳动物Ctr2蛋白在Cu获得中的生理作用将通过对小鼠Ctr2敲除突变体的分析、通过培养细胞中的生物化学和细胞生物学实验以及通过对Ctr2突变蛋白的分析来确定。在第二个具体目标中，将通过分析细胞培养物中Ctr 1 Cu输入子和Ctr 2蛋白的翻译后调节来破译Ctr 1 Cu输入子和Ctr 2蛋白的调节。在第三个具体目标的实验中，概述了一种新的血液传播的信号，允许外周器官，如心脏和铜的采集和存储器官之间的器官间通信。总之，这些调查将破译铜收购机制，其功能是必不可少的正常生长，发育和人类健康的关键功能作用和细胞和系统的调节机制。