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。 锌缺乏严重影响生殖过程，危害胚胎发育，但对锌的体内平衡是如何维持的知之甚少。 具体来说，我们将研究编码锌转运蛋白的基因。 我们将集中在最近确定的三个成员的小鼠ZIP基因超家族的金属转运蛋白。 小鼠ZIP 1、2和3彼此密切相关，并且与最近发现的ZIP超家族人类锌转运蛋白密切相关。 这些ZIP基因负责锌的吸收，并且类似的锌转运蛋白在锌缺乏时上调，并且在低等真核生物中显示细胞特异性表达。 将检查这些mZIP基因在生殖道和胚胎中的分子生物学。 我们将测试的假设，这些锌转运蛋白在哺乳动物锌稳态中发挥重要的生理作用。 因此，本修订提案的具体目标是：1）克隆和表征这些小鼠ZIP基因和cDNA，并检查其转运特性; 2）描绘这些mZIP基因在母体和胚胎组织中表达的时空模式，并检查其通过膳食锌的调节; 3）确定这些mZIP基因的靶向突变对锌稳态的影响。 该项目代表了Andrews、艾德和Palmiter博士实验室之间的合作努力。 私家侦探，Andrews博士是哺乳动物胚胎发育和锌缺乏以及金属硫蛋白基因调控的分子生物学专家。 我的上司，艾德博士是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.