Copper Homeostasis in Mammals

微量元素铜是人体正常生长发育的必需元素，在人体内广泛存在。 执行能量产生、结缔组织等过程的各种生化反应 成熟、神经肽加工、凝血、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，心肌肥大，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。而一些基因和 在酵母和哺乳动物中已经发现了它们相应的蛋白质，这些蛋白质在铜的吸收和释放中发挥作用 在细胞水平上的分布，我们对这些组件的功能的了解有很多空白 哺乳动物生理学。这项建议描述了以小鼠为模型的研究途径 哺乳动物系统，以破译两种哺乳动物铜的作用机制和生理作用 运输蛋白，Ctrl和Ctr2。第一个具体目标是遗传学、细胞生物学和生物化学实验 以了解Ctrl铜导入蛋白在膳食铜获取和代谢中的生理功能。 全身性铜分布。第二个具体目标概述了剖析Ctr2Cu2功能的实验 转运蛋白，它定位于细胞内的囊泡室，在细胞内铜的运输 水平及其在哺乳动物生理学中的作用。总而言之，这些研究将解决我们在 Ctr1和Ctr2铜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，对哺乳动物的正常生长和发育至关重要。

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.