MAMMALIAN COPPER TRANSPORT, HOMEOSTASIS, AND ITS DEFECTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。铜是一种必需但有毒的微量营养素，在许多生理过程和疾病的发展中起着关键作用。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，同时防止有毒的积累和自由反应形式的铜的释放。一个重要的新兴领域是鉴定铜代谢中的组分，并表征它们在实现系统铜稳态中的功能、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稳态铜代谢的机制，并确定导致铜相关疾病的铜代谢缺陷的分子基础。我们对哺乳动物Ctr 1铜转运蛋白的前期研究为研究Ctr 1的功能和异常铜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Ctr 1在系统性铜稳态中的作用，具体目的如下：（1）利用Ctr 1表达水平受遗传调控的小鼠和肠道细胞系，研究Ctr 1在肠道铜吸收中的作用。(2)我们将确定潜在的机制，导致器官特异性铜积累缺陷的Ctr 1杂合（Ctr 1 +/-）小鼠。本研究将阐明Ctr 1的作用和作用方式，以及在实现全身铜稳态中发挥作用的组分之间的相互作用。(3)我们将产生和表征Ctr 1 +/-或Ctr 1过表达小鼠与人威尔逊病（铜毒性疾病）或阿尔茨海默病（具有复杂病因的铜相关疾病）小鼠模型之间的杂交小鼠，以阐明Ctr 1介导的铜摄取缺陷在这些疾病进展中的作用。总的来说，拟议的研究将确定哺乳动物Ctr 1铜转运蛋白在全身铜稳态中的作用，并最终提供关键信息，以制定更好的策略来治疗铜相关疾病。

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.