Copper Homeostasis in Mammals

说明(申请人提供)：微量元素铜(铜)对正常生长和发育至关重要，因为它在执行能量生成、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的各种生化反应中扮演着重要角色。饮食中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、贫血等多种病理生理状态。虽然在酵母和哺乳动物中已经发现了一些在细胞水平上参与铜吸收和分布的基因及其相应的蛋白质，但我们对这些成分在哺乳动物生理中的功能还存在许多空白。这项建议描述了以小鼠为模型哺乳动物系统，破译两种哺乳动物铜转运蛋白Ctr1和Ctr2的作用机制和生理作用的研究途径。在第一个具体目标中，概述了遗传学、细胞生物学和生化实验，以了解Ctrl铜导入蛋白在饲料铜获取和系统铜分布中的生理功能。第二个特定目标概述了Ctr2铜转运蛋白在细胞水平上的功能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在Ctr1和Ctr2铜运输蛋白的调控和生理功能方面的关键知识空白，这些蛋白在驱动对正常哺乳动物生长和发育至关重要的铜依赖的生化反应中发挥作用。

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.