Copper Homeostasis in Mammals

描述（由申请人提供）：微量元素铜（Cu）是正常生长发育所必需的，因为它在多种生化反应中发挥作用，这些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。饮食中缺铜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、心脏肥厚、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。虽然在酵母和哺乳动物中已经发现了一些基因及其相应的蛋白质在细胞水平上对铜的摄取和分布起作用，但我们对这些成分在哺乳动物生理学中的功能的了解还存在许多空白。本文介绍了以小鼠为模型哺乳动物系统的研究途径，以破译两种哺乳动物铜转运蛋白Ctrl和Ctr2的作用机制和生理作用。本文首先通过遗传、细胞生物学和生物化学实验，了解Ctrl型铜进口鸡在饲粮铜获取和全身铜分配中的生理功能。第二个特定目标概述了实验，以剖析定位于细胞内囊泡室的Ctr2铜转运体在细胞水平上的细胞内铜转运及其在哺乳动物生理学中的作用。综上所述，这些研究将填补我们对Ctrl和Ctr2 Cu转运蛋白在驱动Cu依赖的生化反应中的调节和生理功能的知识空白，这些生化反应对正常哺乳动物的生长和发育至关重要。

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.