MAMMALIAN COPPER TRANSPORT, HOMEOSTASIS, AND ITS DEFECTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。铜是一种基本但有毒的微量营养素，在许多生理过程和疾病的发展中发挥着关键作用。生物体必须从饮食中获得铜，并将其输送到需要铜的蛋白质中，同时防止铜的有毒积累和释放。一个重要的新兴领域是确定铜代谢的成分，并表征它们在实现全身铜稳态中的功能、相互作用和调节。我们的长期研究目标是阐明哺乳动物体内铜代谢平衡的机制，并确定导致铜相关疾病的铜代谢缺陷的分子基础。我们以前对哺乳动物铜转运蛋白CTR1的研究为研究CTR1的功能和铜异常转运在疾病中的意义奠定了基础，并提供了新的工具。本研究利用细胞系和小鼠模型研究了CTR1铜转运体在全身铜稳态中的作用，具体目的如下：(1)我们将利用肠道细胞系和CTR1表达水平受基因调控的小鼠，确定CTR1在肠道饮食铜吸收中所起的作用。(2)我们将确定CTR1杂合(CTR1+/-)小鼠器官特异性铜蓄积缺陷的潜在机制。这项研究将阐明CTR1的作用和作用模式，以及在实现全身铜稳态中发挥作用的组件之间的相互作用。(3)我们将建立CTR1+/-或CTR1超表达小鼠与人类肝豆状核变性(一种铜中毒疾病)或阿尔茨海默病(一种铜相关疾病，病因复杂)的小鼠模型，并对其进行杂交，以阐明CTR1介导的铜摄取缺陷在这些疾病进展中的作用。总之，拟议的研究将确定哺乳动物CTR1铜转运体在全身铜稳态中的作用，并最终为开发更好的治疗铜相关疾病的策略提供关键信息。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Copper is an essential, yet toxic micronutrient that plays a critical role in a number of physiological processes and in the development of diseases. Organisms must acquire copper from the diet and deliver it to copper-requiring proteins while preventing toxic accumulation and release of free reactive form of copper. An important emerging area is the identification of the components in copper metabolism and the characterization of their functions, interactions and regulations in achieving systemic copper homeostasis. Our long-term research goals are to elucidate mechanisms of the homeostatic copper metabolism in mammals and to determine the molecular basis of defects in copper metabolism that causes copper-related diseases. Our previous studies on the Ctr1 mammalian copper transporter have laid the foundation and provided novel tools for the investigation of Ctr1 functions and implications of aberrant copper transport in diseases. This proposal addresses the roles of the Ctr1 copper transporter in systemic copper homeostasis using cell lines and mouse models with the following specific aims: (1) We will determine the roles played by Ctr1 in dietary copper absorption in the intestine using an intestinal cell line and mice in which Ctr1 expression levels are genetically modulated. (2) We will identify underlying mechanisms causing organ-specific copper accumulation defects of Ctr1 heterozygous (Ctr1+/-) mice. This study will elucidate the role and mode of actions of Ctr1 and the interactions among components that play roles in achieving systemic copper homeostasis. (3) We will generate and characterize inter-crossed mice between Ctr1+/- or Ctr1 over-expressing mice and mouse model of human Wilson disease (a copper toxicity disease) or Alzheimer¿s disease (a copper -related disease with complex etiology), to elucidate the roles of defects in Ctr1-mediated copper uptake in the progression of these diseases. Collectively, the proposed studies will determine the roles of the mammalian Ctr1 copper transporter in systemic copper homeostasis, and ultimately provide critical information to develop better strategies to treat copper-related disorders.