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。具体地说，我们一直在研究ZIP4基因，该基因突变导致人类罕见的常染色体隐性遗传性肠性肢端皮炎(AE)。ZIP4是溶质载体39A金属转运蛋白超家族的一员，我们发现ZIP5是一个近亲。在这一竞争的继续中，我们建议检验这一假设，即ZIP4和ZIP5在锌的动态平衡中都发挥着重要的生理作用，其中ZIP4是摄取限量膳食锌的主要机制，而ZIP5在锌充足的条件下对锌的去除起主要作用。这些蛋白质具有相反功能的假设是基于我们的发现，它们定位于极化的肠道细胞和内脏内胚层细胞的相对膜上，这两种细胞类型对正常的锌稳态至关重要，并且它们对这些细胞中锌的可利用性表现出相反的反应。在最初的资助阶段，我们发现小鼠ZIP4mRNA的表达以及ZIP4和ZIP5蛋白受到几种新的转录后机制和相反的锌依赖机制的动态调节。我们还发现，小鼠ZIP4基因对早期胚胎发育是必不可少的，单倍体不足会对几个器官系统的发育产生多效性影响，并导致对膳食缺锌的过敏。因此，ZIP4是一个非常重要的基因，值得进一步研究。目前还没有关于ZIP5功能的遗传数据，但它对锌的依赖调节与ZIP4相反，表明它可能是非常重要的。为了进一步研究这些锌转运蛋白的调控功能和机制，我们将追求以下具体目标：1)确定组织特异性条件敲除ZIP4和/或Zip5基因对小鼠锌稳态的影响；2)探索ZIP4和ZIP5转录后锌调控的锌依赖机制。这些研究将有助于我们理解致命的人类遗传性疾病肠性肢端皮炎，并为几种出生缺陷的病因提供重要的见解，以及有助于我们对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理解称为肠性肢端皮炎(AE)的致命人类遗传性疾病。了解这种疾病背后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。在全球范围内，这些研究将有助于我们对哺乳动物体内必需金属锌的动态平衡的分子机制有基本的了解。

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.