Molecular Biology of Mammalian Zinc Homeostasis

这些研究的总体长期目标是阐明小鼠妊娠和胚胎发育期间锌稳态的分子机制。锌缺乏深刻地影响生殖过程和危害胚胎发育，但很少知道锌是如何维持稳态的。具体来说，我们将研究编码锌转运蛋白的基因。我们将重点研究最近发现的小鼠ZIP基因金属转运蛋白超家族的三个成员。小鼠ZIP1、2和3彼此密切相关，并与最近发现的人类ZIP超家族锌转运蛋白密切相关。这些ZIP基因负责锌摄取和类似的锌转运蛋白在缺锌时被上调，并在低等真核生物中表现出细胞特异性表达。研究这些mZIP基因在生殖道和胚胎中的分子生物学特性。我们将测试这些锌转运蛋白在哺乳动物锌稳态中发挥核心生理作用的假设。因此，这项订正建议的具体目的是：1)克隆并鉴定这些小鼠ZIP基因和cdna，并检测其转运特性；2)明确mZIP基因在母体和胚胎组织中的时空表达模式，并研究膳食锌对其表达的调节作用；3)确定mZIP基因靶向突变对锌稳态的影响。这个项目代表了博士实验室之间的合作努力。安德鲁斯，艾德和帕尔米特。安德鲁斯博士是哺乳动物胚胎发育和锌缺乏症方面的专家，也是金属硫蛋白基因调控的分子生物学专家。共同。Eide博士是ZIP转运功能领域的专家和领导者，我们的合作者Palmiter博士是小鼠基因靶向方面的专家。

The overall long-term objective of these studies is to elucidate the molecular mechanisms involved in zinc homeostasis in mice during pregnancy and embryonic development. Zinc deficiency profoundly affects reproductive processes and jeopardizes embryonic development, yet little is known about how zinc homeostasis is maintained. Specifically, we will study genes which encode zinc transporters. We will focus on three recently identified members of the mouse ZIP gene superfamily of metal transporters. Mouse ZIP1, 2 and 3 are closely related to each other and to recently identified human zinc transporters of the ZIP superfamily. These ZIP genes are responsible for zinc uptake and similar zinc transporters are up-regulated by zinc deficiency and display cell-specific expression in lower eukaryotes. The molecular biology of these mZIP genes in the reproductive tract and embryo will be examined. We will test the hypothesis that these zinc transporters play a central physiological role in zinc homeostasis in mammals. Therefore, the specific aims of this revised proposal are to; 1) clone and characterize these mouse ZIP genes and cDNAs, and examine their transport properties; 2) delineate the temporal-spatial patterns of expression of these mZIP genes in maternal and embryonic tissues, and examine their regulation by dietary zinc, and 3) determine the affects of targeted mutations of these mZIP genes on zinc homeostasis. This project represents a collaborative effort between the laboratories of Drs. Andrews, Eide and Palmiter. The P.I., Dr. Andrews is an expert in mammalian embryonic development and zinc deficiency, and in the molecular biology of metallothionein gene regulation. The co-I., Dr. Eide is an expert and leader in the field of ZIP transport function, and our collaborator, Dr. Palmiter is an expert in gene targeting in mice.