A mouse model of acrodermatitis enteropathica

肠病性肢端皮炎小鼠模型

基本信息

批准号：
8054837
负责人：
GLEN K ANDREWS
金额：
$ 30.62万
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 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8054837
关键词：
3&apos Untranslated Regions A Mouse Acinar Cell Address Affect Alleles Animals Biochemical Birth Blood Cells Congenital Abnormality Conserved Sequence Data Development Diet Dietary Zinc Disease Embryonic Development Endoderm Cell Enterocytes Etiology Excision Extracellular Domain Funding Gene Expression Regulation Gene Mutation Genes Genetic Health Hereditary Disease Homeostasis Human Human Genetics Hypersensitivity Intestines Investigation Ions Knock-out Knockout Mice Mammals Maps Membrane Messenger RNA Metals Molecular Mus Mutate Mutation N-terminal Pancreas Patients Phenotype Physiological Play Process Proteins Publishing Regulation Relative (related person)Research Role Site Structure Testing Tissues Visceral Zinc Zinc deficiency acrodermatitis enteropathica autosomal recessive trait base body system cell type gene function in vivo insight mRNA Expression member mouse model novel response solute stem uptake 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. Specifically, we have been studying the Zip4 gene, mutations in which cause the rare, autosomal recessive trait acrodermatitis enteropathica (AE), in humans. ZIP4 is a member of the solute carrier 39a superfamily of metal transporters, and we find that ZIP5 is a close relative. In this competing continuation, we propose to test the hypothesis that ZIP4 and ZIP5 both play central physiological roles in zinc homeostasis with ZIP4 being the major mechanism for uptake of limiting dietary zinc while ZIP5 plays a major role in the removal of zinc under zinc-replete conditions. The hypothesis that these proteins have opposing functions is based on our finding that they localize to opposite membranes of polarized intestinal enterocytes and visceral endoderm cells, cell-types critical for proper zinc homeostasis, and they show opposite responses to zinc availability in these cells. In the initial funding period we discovered that mouse Zip4 mRNA expression and ZIP4 and ZIP5 proteins are dynamically regulated by several novel posttranscriptional and opposing zinc-dependent mechanisms. We also discovered that the mouse Zip4 gene is essential for early embryonic development and that haploinsufficiency exerts pleiotropic effects on the development of several organ systems and causes hypersensitivity to dietary zinc deficiency. Thus, Zip4 is a critically important gene that warrants further investigation. There are no genetic data on ZIP5 function but its zinc-dependent regulation opposite to that of ZIP4 suggests that it may be very important. To further address the functions and mechanisms of regulation of these zinc transporters we will pursue the following specific aims: 1) Determine the effects of tissue-specific conditional knockouts of the Zip4 and/or Zip5 genes on zinc homeostasis in the mouse, and 2) Explore the zinc-dependent mechanisms of posttranscriptional zinc-regulation of ZIP4 and ZIP5. These studies will contribute to our understanding of the lethal human genetic disorder acrodermatitis enteropathica and provide important insights into the etiology of several birth defects, as well as contribute to our basic understanding of the molecular mechanisms governing mammalian zinc homeostasis. PUBLIC HEALTH RELEVANCE: These studies will contribute to our understanding of the lethal human genetic disorder called acrodermatitis enteropathica (AE). Understanding the molecular mechanisms that underlie this disease will also provide important insights into the etiology of several birth defects that we discovered to be associated with mutations of the AE gene in mice. In a global sense, these studies will contribute to our basic understanding of the molecular mechanisms governing the homeostasis of the essential metal zinc in mammals.

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。具体而言，我们一直在研究Zip4基因，其中引起人类中罕见的常染色体隐性性状性脂肪炎（AE）。 Zip4是金属转运蛋白的溶质载体39a超家族的成员，我们发现Zip5是近亲。在这种竞争延续中，我们建议测试以下假设：Zip4和Zip5均在锌稳态中起主要的生理作用，而Zip4是摄取限制饮食锌的主要机制，而ZIP5在锌复制条件下ZINC的去除中起主要作用。这些蛋白质具有相反功能的假设是基于我们的发现，即它们定位于极化肠肠上皮细胞和内脏内胚层细胞的相反膜，对于适当的锌稳态至关重要的细胞类型，并且它们对这些细胞中锌的可用性的反应相反。在最初的资金期间，我们发现小鼠zip4 mRNA表达，Zip4和Zip5蛋白受到几种新型的转录后和相反的锌依赖性机制的动态调节。我们还发现，小鼠Zip4基因对于早期胚胎发育至关重要，单倍不足易于对多个器官系统的发育产生多效性影响，并导致对饮食锌缺乏的超敏反应。因此，Zip4是一个至关重要的基因，需要进一步研究。没有关于Zip5功能的遗传数据，但其锌依赖性调节与Zip4相反的调节表明它可能非常重要。为了进一步解决这些锌转运蛋白调节的功能和机制，我们将追求以下具体目的：1）确定Zip4和/或Zip5基因对鼠标锌稳态的组织特异性条件敲除对鼠标锌稳态的影响，而2）探索ZIPS-ZIP-4和ZIP4和ZIP5的ZINC依赖性机制。这些研究将有助于我们理解肠道疾病的致命性人类遗传疾病炎症性炎症性炎性疾病，并为几种先天缺陷的病因提供重要的见解，并有助于我们对管理哺乳动物锌稳态的分子机制的基本理解。公共卫生相关性：这些研究将有助于我们对称为脂肪炎的致命人类遗传疾病（AE）的理解。了解这种疾病基础的分子机制还将为我们发现与小鼠中AE基因突变有关的几种出生缺陷的病因提供重要的见解。从全球意义上讲，这些研究将有助于我们对哺乳动物基本金属锌稳态的分子机制的基本理解。