Copper Homeostasis in Mammals

描述（由申请人提供）：微量元素铜（Cu）是正常生长和发育所必需的，因为其在各种生化反应中发挥作用，这些反应进行能量产生、结缔组织成熟、神经肽加工、凝血、铁分布和氧化应激保护等过程。膳食铜缺乏或铜稳态疾病导致运动功能受损、严重认知障碍、胚胎和新生儿发育异常、心脏肥大、血管生成缺陷和主动脉弹性降低、贫血和许多其他病理生理状态。虽然已经在酵母和哺乳动物中鉴定出在细胞水平上在Cu吸收和分布中起作用的许多基因及其相应的蛋白质，但我们对这些组分在哺乳动物生理学中的功能的认识存在许多空白。该提案描述了调查的途径，使用小鼠作为模型哺乳动物系统，以破译两种哺乳动物铜转运蛋白，Ctrl和Ctr2的作用和生理作用的机制。在第一个特定的目标遗传，细胞生物学和生化实验概述了了解的生理功能的控制铜进口商在饮食中的铜收购和系统铜分布。第二个具体的目标概述了实验解剖的Ctr2铜转运蛋白，它定位于细胞内囊泡室，在细胞内铜运输在细胞水平和其在哺乳动物生理学中的作用的功能。总之，这些研究将解决关键的差距，我们的知识的调控和生理功能的Ctrl和Ctr2铜转运蛋白在驱动铜依赖的生化反应，是至关重要的正常哺乳动物的生长和发育。

DESCRIPTION (provided by applicant): 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.