Mammalian Zinc Transporters and Zinc Homeostasis

哺乳动物锌转运蛋白和锌稳态

• 批准号: 8322785
• 负责人: David J Eide
• 金额: $ 22.79万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322785
• 关键词: Address; Affect; Animal Model; Attention; Carrier Proteins; Cell physiology; Cells; Collagen; Connective Tissue Diseases; Defect; Disease; Ehlers-Danlos Syndrome; Endoplasmic Reticulum; Environment; Family; Genes; Health; Homeostasis; Human; Hydroxylation; Ions; Lead; Link; Mammalian Cell; Mammals; Metals; Mitochondria; Modeling; Modification; Molecular; Mutation; Organelles; Patients; Physiology; Play; Process; Proteins; Role; Site; System; Testing; Vacuole; Vesicle; Yeasts; Zinc; Zinc deficiency; cell type; cofactor; insight; interest; member; novel; public health relevance; research study; uptake; zinc-binding protein

DESCRIPTION (provided by applicant): As our understanding of zinc homeostasis in model organisms such as yeast becomes increasingly detailed, we still know very little about many basic aspects of zinc homeostasis in human cells. To address some of these questions, we have focused our studies on Zip13, the product of the SLC39A13 gene. Zip13 is a member of the ZIP family of metal ion transporters. Surprisingly, mutations in SLC39A13 were recently identified as causing a form of Ehlers-Danlos Syndrome (EDS), a connective tissue disease that results from defects in collagen modification and assembly. Given this intriguing link between Zip13 and EDS, it was of interest to us how a metal ion transporter contributes to this disease. In preliminary experiments, we have found that Zip13 is a zinc-specific transporter that localizes to a vesicular organelle in a wide variety of human cell types. The identity of these vesicles is not yet known. We propose the hypothesis that these vesicles are storage sites for zinc and that Zip13 is responsible for transporting this stored zinc out of those compartments under conditions of zinc deficiency. We further hypothesize that the defects in collagen assembly seen in EDS patients with SLC39A13 mutations result from ER zinc deficiency due to the trapping of zinc within its storage organelle. To test these hypotheses, we will a) assess the impact of Zip13 on cellular zinc homeostasis, b) determine the effect of Zip13 disruption on ER function, collagen hydroxylation, and ER zinc status, and c) determine whether Zip13 co-localizes to the zincosome, a vesicular site of zinc storage. Pursuit of these aims provides a unique opportunity to assess the function of vesicular zinc storage in mammalian zinc homeostasis. Zip13 may provide the first molecular handle with which to identify the organellar sites of zinc storage and characterize their function in mammalian cells. PUBLIC HEALTH RELEVANCE: The processes of intracellular zinc transport and homeostasis are essential for basic cellular function, physiology, and human health. Despite this importance, however, we still know little about the specific transporter proteins involved and how they function in maintaining zinc homeostasis in human cells. This proposal is focused on Zip13, a zinc transporter recently linked to some cases of Ehlers-Danlos Syndrome, and the role this protein plays in controlling the vesicular storage of zinc.

描述（由申请人提供）：随着我们对诸如酵母菌模型生物中锌稳态的理解变得越来越详细，我们仍然对人类细胞中锌稳态的许多基本方面知之甚少。为了解决其中一些问题，我们将研究重点放在SLC39A13基因的产物Zip13上。 Zip13是金属离子转运蛋白的拉链家族的成员。令人惊讶的是，SLC39A13中的突变最近被确定为引起一种形式的Ehlers-Danlos综合征（EDS），这是一种结缔组织疾病，是由于胶原蛋白修饰和组装缺陷而导致的结缔组织疾病。鉴于Zip13和ED之间的这种有趣的联系，我们感兴趣的是金属离子转运蛋白如何促进该疾病。在初步实验中，我们发现Zip13是一种锌特异性转运蛋白，它将其定位于各种人类细胞类型的囊泡细胞器。这些囊泡的身份尚不清楚。我们提出了这样的假设，即这些囊泡是锌的储存位点，Zip13负责在锌缺乏条件下从这些隔室中运送出该储存的锌。我们进一步假设，由于锌在其储存细胞器中捕获的ER锌缺乏引起的EDS患者EDS患者的胶原蛋白组件缺陷。为了检验这些假设，我们将a）评估Zip13对细胞锌稳态的影响，b）确定Zip13破坏对ER功能，胶原羟基化和ER锌状态的影响，以及C）确定Zip13是否共同定位于锌，锌的囊泡位点。对这些目标的追求为评估哺乳动物锌稳态中囊泡锌储存功能的功能提供了独特的机会。 ZIP13可以提供第一个分子手柄，以鉴定锌存储的细胞器位点并表征其在哺乳动物细胞中的功能。 公共卫生相关性：细胞内锌运输和稳态的过程对于基本的细胞功能，生理和人类健康至关重要。但是，尽管如此，我们仍然对所涉及的特定转运蛋白以及它们在维持人类细胞中锌稳态方面的作用知之甚少。该提案的重点是Zip13，这是一种与某些Ehlers-Danlos综合征相关的锌转运蛋白，该蛋白质在控制锌的水泡储存方面所起的作用。