A Mouse Model of Acrodermatitis Enteropathica

肠病性肢端皮炎小鼠模型

• 批准号: 6729892
• 负责人: GLEN K ANDREWS
• 金额: $ 27.42万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729892
• 关键词: acrodermatitis enteropathica; cell membrane; complementary DNA; confocal scanning microscopy; dietary trace element; disease /disorder model; gastrointestinal absorption /transport; gene expression; gene mutation; gene targeting; genetically modified animals; green fluorescent proteins; laboratory mouse; messenger RNA; metal metabolism; northern blottings; nutrition; nutrition related tag; polymerase chain reaction; tissue /cell culture; western blottings; zinc

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.

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中锌稳态涉及的分子机制。在此，我们建议研究罕见的常染色体隐性性状，肠炎肠炎（AE）。 AE的结果是无法吸收明显的饮食锌，并且刚刚发现了AE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，并被称为HZIP4。我们将检验以下假设：这种推定的锌转运蛋白使用小鼠模型在锌稳态中起着中心的生理作用。没有用于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，确定它在肠道中高度表达，并证明MZIP4 mRNA在饮食锌缺乏时期被大大上调。因此，该提案的具体目的是：1）描述MZIP4天然和AE突变体的金属转运特性； 2）阐明MZIP4表达的金属调节机制； 3）确定MZIP4基因靶向突变对小鼠锌稳态的影响。该项目代表了博士实验室之间的协作努力。安德鲁斯，埃德和彼得森。 P.I. Andrews博士是哺乳动物胚胎发育和锌缺乏症的专家，以及基因表达的金属调节。 Eide博士是邮政运输函数和调节领域的专家和领导者，以及彼得森博士是Globin基因座调节和小鼠敲除策略的专家。