Copper Homeostasis in Mammals

哺乳动物的铜稳态

• 批准号: 7367133
• 负责人: Dennis J Thiele
• 金额: $ 25.98万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367133
• 关键词: Address; Affinity; Anemia; Area; Automobile Driving; Biochemical; Biochemical Reaction; Blood Clot; Blood coagulation; Carrier Proteins; Cell membrane; Cellular biology; Cognition Disorders; Connective Tissue; Copper; Cultured Cells; Data; Development; Disease; Elasticity; Embryo; Employee Strikes; Enzymes; Generations; Genes; Genetic; Growth and Development function; Heart Hypertrophy; Homeostasis; Human; Investigation; Iron; Knockout Mice; Knowledge; Localized; Mammals; Micronutrients; Modeling; Molecular Chaperones; Motor; Mus; Neonatal; Neuropeptides; Numbers; Oxidative Stress; Physiological; Physiology; Play; Process; Proteins; Regulation; Role; Saccharomyces cerevisiae; System; Tissues; Trace Elements; Vacuole; Vesicle; Work; Yeasts; angiogenesis; deprivation; in vivo; research study; uptake

The trace element copper (Cu) is essential for normal growth and development due to its role in a wide variety of biochemical reactions that carry out processes including energy generation, connective tissue maturation, neuropeptide processing, blood clotting, iron distribution and oxidative stress protection. Dietary Cu deprivation or diseases of Cu homeostasis result in impaired motor function, severe cognitive disorders, embryonic and neonatal developmental abnormalities, cardiac hypertrophy, defective angiogenesis and reduced aortic elasticity, anemia and many other pathophysiological states. While a number of genes and their corresponding proteins have been identified in yeast and mammals that function in Cu uptake and distribution at the cellular level, there are many gaps in our knowledge of the function of these components in mammalian physiology. This proposal describes avenues of investigation, using mice as a model mammalian system, to decipher the mechanisms of action and physiological roles of two mammalian Cu transport proteins, Ctrl and Ctr2. In the first specific aim genetic, cell biology and biochemical experiments are outlined to understand the physiological functions of the Ctrl Cu importer in dietary Cu acquisition and in systemic Cu distribution. The second specific aim outlines experiments to dissect the function of the Ctr2 Cu transporter, which localizes to intracellular vesicular compartments, in intracellular Cu transport at the cellular level and its role in mammalian physiology. Taken together, these studies will address critical gaps in our knowledge on the regulation and physiological function of the Ctrl and Ctr2 Cu transport proteins in driving Cu-dependent biochemical reactions that are critical for normal mammalian growth and development.

微量元素铜（Cu）由于其在广泛的环境中的作用，对正常生长和发育至关重要。 各种生化反应，包括能量产生，结缔组织 成熟、神经肽加工、血液凝固、铁分布和氧化应激保护。膳食 铜缺乏或铜稳态疾病会导致运动功能受损、严重的认知障碍， 胚胎和新生儿发育异常，心脏肥大，血管生成缺陷， 主动脉弹性降低、贫血和许多其他病理生理状态。虽然一些基因和 在酵母和哺乳动物中已经鉴定出它们的相应蛋白质，其在Cu吸收中起作用， 虽然在细胞水平上的分布，但我们对这些成分在细胞中的功能的认识存在许多空白。 哺乳动物生理学该提案描述了使用小鼠作为模型的研究途径 哺乳动物系统，破译两种哺乳动物铜的作用机制和生理作用 转运蛋白，Ctrl和Ctr2。在第一个特定目标的遗传学，细胞生物学和生物化学实验 的生理功能，以了解控制铜进口商在膳食铜的收购和 Cu的系统分布第二个具体目标概述了解剖Ctr2 Cu功能的实验 转运蛋白，定位于细胞内囊泡区室，在细胞内铜转运中， 水平及其在哺乳动物生理学中的作用。总之，这些研究将解决我们的关键差距， 对Ctrl和Ctr2 Cu转运蛋白在驾驶中的调节和生理功能的认识 铜依赖的生化反应，对正常哺乳动物的生长和发育至关重要。