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.

痕量元素铜（CU）对于正常生长和发育至关重要，因为它在宽阔的 多种生化反应进行，包括能量产生，结缔组织在内的过程 成熟，神经肽加工，血液凝结，铁分布和氧化应激保护。饮食 CU剥夺或CU稳态疾病导致运动功能受损，严重的认知障碍， 胚胎和新生儿发育异常，心脏肥大，缺陷血管生成和 降低主动脉弹性，贫血和许多其他病理生理状态。而许多基因和 它们相应的蛋白质已在酵母和哺乳动物中鉴定出来，这些蛋白质在Cu摄取中起作用，并且 在细胞级别的分布，我们对这些成分功能的知识有很多差距 哺乳动物生理学。该建议描述了调查的途径，使用小鼠作为模型 哺乳动物系统，破译了两个哺乳动物Cu的作用机理和生理作用 转运蛋白，CTRL和CTR2。在第一个特定的目标遗传学，细胞生物学和生化实验中 概述以了解Ctrl Cu进口商在饮食cu习得和中的生理功能 系统性CU分布。第二个特定目的概述了剖析CTR2 Cu功能的实验 转运蛋白位于细胞内囊泡室的转运蛋白，在细胞内CU转运 水平及其在哺乳动物生理学中的作用。综上所述，这些研究将解决我们的关键差距 关于CTRL和CTR2 CU转运蛋白在驾驶中的调节和生理功能的知识 CU依赖性的生化反应对于正常的哺乳动物生长和发育至关重要。