Copper Homeostasis in Mammals

哺乳动物的铜稳态

• 批准号: 8519990
• 负责人: Dennis J Thiele
• 金额: $ 32.52万
• 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/8519990
• 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）扮演着对正常生长，发育和健康至关重要的生化反应的关键催化和调节功能。 Menkes病和威尔逊氏病是CU代谢的两种严重的人类遗传疾病，分别导致儿童死亡率以及肝和神经功能障碍。不适当的铜平衡与骨髓病，prion病，阿尔茨海默氏病和心血管疾病和癌症有关。因此，了解细胞控制CU的获取，分布和利用的机制至关重要。尽管CU进口的识别和功能，但细胞内分布和外排机械开始被理解，但我们对CTR2蛋白的生理作用知之甚少，CU进口的调节以及生物体如何建立全球CU稳态。在本应用中概述了三个具体目标，这些目标与他们将根据哺乳动物Cu运输机制的作用机理的信息相互关联，及其在细胞和系统水平上的调节。在第一个特定目标中，将通过分析小鼠CTR2敲除突变体，通过生化和细胞生物学实验在培养的细胞中和CTR2突变蛋白的分析来确定哺乳动物CTR2蛋白在CU获得中的生理作用。在第二个特定目的中，CTR1 Cu进口商的调节和CTR2蛋白将通过分析其在细胞培养中的转化后调节来解密。在第三个特定的目标实验中，概述了一个新型的血液传播信号，该信号允许外围器官（例如心脏，铜，储存器官和储存器官）之间的孔间通信。综上所述，这些研究将破译关键功能作用以及CU采集机制的细胞和全身调节机制，其功能对于正常生长，发育和人类健康至关重要。