A mouse model of acrodermatitis enteropathica

肠病性肢端皮炎小鼠模型

基本信息

批准号：
7788831
负责人：
GLEN K ANDREWS
金额：
$ 30.93万
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/7788831
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 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 public health relevance 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锌稳态的分子机制。具体来说，我们一直在研究 Zip4 基因，该基因的突变会导致人类罕见的常染色体隐性遗传性肢端皮炎肠病 (AE)。 ZIP4 是金属转运蛋白溶质载体 39a 超家族的成员，我们发现 ZIP5 是近亲。在这个竞争性的延续中，我们建议检验以下假设：ZIP4和ZIP5在锌稳态中都发挥着重要的生理作用，其中ZIP4是吸收限制性膳食锌的主要机制，而ZIP5在锌充足的情况下去除锌中起着主要作用状况。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上皮细胞和内脏内胚层细胞的相对膜，这些细胞类型对于适当的锌稳态至关重要，并且它们对这些细胞中的锌可用性表现出相反的反应。在最初的资助期间，我们发现小鼠 Zip4 mRNA 表达以及 ZIP4 和 ZIP5 蛋白受到几种新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，单倍体不足对多个器官系统的发育产生多效性影响，并导致对饮食缺锌的过敏。因此，Zip4 是一个极其重要的基因，值得进一步研究。目前还没有关于 ZIP5 功能的遗传数据，但其与 ZIP4 相反的锌依赖性调节表明它可能非常重要。为了进一步研究这些锌转运蛋白的功能和调节机制，我们将追求以下具体目标：1) 确定 Zip4 和/或 Zip5 基因的组织特异性条件敲除对小鼠锌稳态的影响，以及 2)探索 ZIP4 和 ZIP5 转录后锌调节的锌依赖性机制。这些研究将有助于我们了解致命的人类遗传性疾病肠病性肢端皮炎，并为几种出生缺陷的病因学提供重要见解，并有助于我们对控制哺乳动物锌稳态的分子机制的基本了解。公共卫生相关性：这些研究将有助于我们了解致命的人类遗传性疾病，即肠病性肢端皮炎 (AE)。了解这种疾病的分子机制也将为我们发现与小鼠 AE 基因突变有关的几种出生缺陷的病因学提供重要的见解。从全球角度来看，这些研究将有助于我们对哺乳动物必需金属锌稳态的分子机制的基本了解。