A Mouse Model of Acrodermatitis Enteropathica

描述（由申请人提供）：我们研究的总体长期目标是阐明哺乳动物锌稳态的分子机制。在此，我们建议研究罕见的，常染色体隐性遗传性状，肠病性肢端皮炎（AE）。AE导致不能吸收显著的膳食锌，并且刚刚鉴定出在患有AE的人类患者中突变的候选基因。该基因编码金属转运蛋白的ZIP基因超家族的成员，并被命名为hZIP 4。我们将测试的假设，这种假定的锌转运蛋白锌稳态中发挥着重要的生理作用，使用小鼠模型。没有AE的小鼠模型存在，基本上对ZIP 4的调节和功能一无所知。在初步研究中，我们克隆了小鼠ZIP 4基因和cDNA，确定它在肠道中高度表达，并证明在膳食锌缺乏期间，mZIP 4 mRNA显著上调。因此，本提案的具体目的是：1）描述mZIP 4的天然和AE突变体的金属转运特性; 2）阐明mZIP 4表达的金属调节机制; 3）确定mZIP 4基因的靶向突变对小鼠锌稳态的影响。该项目代表了Andrews、艾德和Peterson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基因表达的金属调节方面的专家。我的上司，艾德博士是ZIP转运蛋白功能和调节领域的专家和领导者，彼得森博士是珠蛋白基因座调控和小鼠基因敲除策略的专家。

DESCRIPTION (provided by applicant): The overall long-term objective of our studies is to elucidate the molecular mechanisms involved in zinc homeostasis in mammals. Herein, we propose to study the rare, autosomal recessive trait, acrodermatitis enteropathic (AE). AE results for the inability to absorb significant dietary zinc, and a candidate gene mutated in human patients with AE was just identified. This gene encodes a member of the ZIP gene superfamily of metal transporters and was named hZIP4. We will test the hypothesis that this putative zinc transporter plays a central physiological role in zinc homeostasis using the mouse model. No mouse models for AE exist and essentially nothing is known about the regulation and functions of ZIP4. In preliminary studies, we have cloned the mouse ZIP4 gene and cDNA, determined that it is highly expressed in the intestinal tract, and demonstrated that mZIP4 mRNA is dramatically up-regulated during periods of dietary zinc deficiency. Therefore, the specific aims of this proposal are to: 1) Delineate the metal transport properties of native and AE mutants of mZIP4; 2) elucidate the mechanisms of metallo-regulation of mZIP4 expression; and 3) determine the affects of targeted mutation of the mZIP4 gene on zinc homeostasis in the mouse. This project represents a collaborative effort between the laboratories of Drs. Andrews, Eide, and Peterson. The P.I., Dr. Andrews is an expert in mammalian embryonic development and zinc deficiency, and in metalloregulation of gene expression. The Co-I., Dr. Eide is an expert and leader in the field of ZIP transporter function and regulation, and Co-I., Dr. Peterson is an expert in globin locus regulation and mouse knockout strategies.