Molecular Mechanisms of ATP-dependent Copper Transporters

项目摘要 铜稳态对心脏的正常发育和功能起着至关重要的作用， 血管和中枢神经系统、胆固醇代谢和免疫反应。中的主要角色 人类细胞内铜平衡的维持属于铜转运酶(Cu2+-ATPase)的一种。 ATPase)ATP7A和ATP7B。我们最近发现了以前未知的角色 肠道ATP7B在维持结肠形态和铜分布中的作用。来描述这些新的 ATP7B在生理相关环境中的功能我们建立了一个新的实验系统 以原代三维肠状突为基础，确定了三个主要的实验目标。这个 在特定目标1下提出的实验将确定ATP7B在饮食调节中的作用 十二指肠对铜的摄取和铜依赖酶的激活。特定目标2将 表征ATP7B的囊泡间转运新途径，并阐明ATP7B参与的机制 ATP7B在小泡之间运动。根据特定目标3的研究将确定如何灭活 ATP7B会引起结肠的病理变化。拟议中的实验将开发出基本的 与哺乳动物铜稳态生理调节相关的概念。结果在意料之中 以促进已知的和新出现的铜失衡疾病的治疗方法的开发。

Project Summary Copper homeostasis plays an essential role in a normal development and function of the cardiac, vascular, and central nervous systems, cholesterol metabolism, and immune response. The main role in the maintenance of copper balance in human cells belongs to the copper-transporting ATPases (Cu- ATPases) ATP7A and ATP7B. We have recently discovered the previously unknown roles for the intestinal ATP7B in maintaining colon morphology and Cu distribution. To characterize these new functions of ATP7B in a physiologically relevant context we have established a novel experimental system based on primary three-dimensional enteroids and defined three main experimental goals. The experiments proposed under Specific Aim 1 will determine the role of ATP7B in regulation of the dietary copper uptake and activation of copper-dependent enzymes in the duodenum. Specific Aim 2 will characterize the novel inter-vesicular route of ATP7B trafficking and elucidate the mechanisms involved in ATP7B movement between the vesicles. Studies under Specific Aim 3 will establish how inactivation of ATP7B causes pathologic changes in the colon. The proposed experiments will develop the fundamental concepts related to physiologic regulation of a mammalian copper homeostasis. The results are expected to facilitate the development of treatments for the known and emerging disorders of copper misbalance.