A Mouse Model of Acrodermatitis Enteropathica

肠病性肢端皮炎小鼠模型

基本信息

批准号：
7174202
负责人：
GLEN K ANDREWS
金额：
$ 26万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7174202
关键词：
A Mouse Acrodermatitis Address Affect Arabidopsis Biological Assay Biology Birds Breeding CCL21 gene Candidate Disease Gene Cell Line Cell membrane Cell physiology Cells Chromosome Mapping Code Complementary DNA Cultured Cells Dependence Dermatitis Dermatologic Detection Diarrhea Dietary Zinc Disease Embryonic Development Eukaryota Eukaryotic Cell Exons Experimental Animal Model Familial disease Family Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Recombination Globin Growth Histidine Homeostasis Human Human Genome Immune System Diseases In Vitro Individual Injection of therapeutic agent Intestinal Absorption Intestines Introns Ions Iron K562 Cells Knock-out Knockout Mice Laboratories Left Lesion Localized Location Mammals Mediating Membrane Messenger RNA Metabolism Metals Methodology Molecular Mucous Membrane Mus Mutate Mutation Names Nomenclature Northern Blotting Patients Physiological Plant Roots Play Process Promoter Regions Property Protein Biosynthesis Proteins Puromycin RNA Regulation Reporter Genes Resources Role Site Small Intestines Specificity Symptoms Testing Transcript Transfection Transgenes Transgenic Organisms Up-Regulation Weight Gain Yeasts ZIP protein Zinc Zinc Sulfate Zinc deficiency Zip Code acrodermatitis enteropathica autosomal recessive trait base blastocyst design embryonic stem cell expression vector homologous recombination in vivo inhibitor/antagonist insight knockout gene mRNA Stability member mouse model mutant novel promoter recessive genetic trait recombinase response uptake vector zinc-binding protein

项目摘要

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 结果表明无法吸收大量膳食锌，并且刚刚确定了人类 AE 患者中的一个候选基因突变。该基因编码金属转运蛋白 ZIP 基因超家族的成员，被命名为 hZIP4。我们将使用小鼠模型检验这种假定的锌转运蛋白在锌稳态中发挥核心生理作用的假设。不存在 AE 小鼠模型，并且基本上对 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mZIP4 mRNA在膳食缺锌期间显着上调。因此，本提案的具体目标是： 1) 描述 mZIP4 天然突变体和 AE 突变体的金属传输特性； 2) 阐明mZIP4表达的金属调控机制； 3) 确定 mZIP4 基因的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合作努力。安德鲁斯、艾德和彼得森。首席研究员安德鲁斯博士是哺乳动物胚胎发育和锌缺乏以及基因表达金属调控方面的专家。联合创始人 Eide 博士是 ZIP 转运蛋白功能和调控领域的专家和领导者，联合创始人 Peterson 博士是珠蛋白基因座调控和小鼠敲除策略方面的专家。