A Mouse Model of Acrodermatitis Enteropathica

描述(申请人提供)：我们研究的总体长期目标是阐明哺乳动物体内锌稳态的分子机制。在这里，我们建议研究罕见的常染色体隐性性状，肠性肢端皮炎(AE)。AE导致无法吸收大量的膳食锌，人类AE患者的一个候选基因突变刚刚被鉴定出来。该基因编码金属转运蛋白ZIP基因超家族成员，命名为hZIP4。我们将使用小鼠模型来验证这个假定的锌转运蛋白在锌的动态平衡中发挥中心生理作用的假设。目前还不存在AE的小鼠模型，基本上对ZIP4的调节和功能一无所知。在初步研究中，我们克隆了小鼠ZIP4基因和cDNA，确定其在肠道中高表达，并证明了mZIP4基因在饮食缺锌期间显著上调。因此，本研究的具体目的是：1)阐明mZIP4天然突变体和AE突变体的金属转运特性；2)阐明金属调控mZIP4表达的机制；3)确定mZIP4基因的靶向突变对小鼠体内锌稳态的影响。这个项目代表了安德鲁斯博士、艾德博士和彼得森博士的实验室之间的合作努力。这位P.I.安德鲁斯博士是哺乳动物胚胎发育和缺锌以及基因表达的金属调控方面的专家。艾德博士是ZIP转运蛋白功能和调控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方面的专家。

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.