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Selenoproteins in Arsenic-Induced Metabolic Dysfunction

砷引起的代谢功能障碍中的硒蛋白

基本信息

批准号：
10328235
负责人：
Robert M Sargis
金额：
$ 49.94万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328235
关键词：
5&apos -AMP-activated protein kinase Address Adverse effects Alleles Architecture Arsenic Beta Cell Binding Proteins Bioenergetics Biological Biological Process Cell Line Cell division Cell physiology Cells Chemicals Data Defect Development Diabetes Mellitus Elements Energy Metabolism Environmental Pollutants Environmental Pollution Enzymes Epidemic Epidemiology Exposure to Fluorescence Microscopy Functional disorder Generations Genetic Polymorphism Glucose Intolerance Glycolysis Goals Health Homeostasis Human Hyperglycemia Imaging Techniques Impairment Individual Insulin Islets of Langerhans Knock-out Knockout Mice Knowledge Link Maps Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Metals Mitochondria Oxidation-Reduction Oxidative Stress Pancreas Pathway interactions Persons Physiological Physiology Play Population Protein Kinase Proteins Public Health Recovery Respiration Risk Risk Factors Roentgen Rays Role Selenium Stress Structure of beta Cell of islet Supplementation Synchrotrons System Testing Therapeutic Therapeutic Intervention Thyroid Hormones Tissues Toxic Environmental Substances Toxic effect United States Variant Viral Vulnerable Populations animal data base blood glucose regulation contaminated drinking water diabetes risk diabetogenic epidemiologic data genetic variant glucose metabolism glucose tolerance glutathione peroxidase hormone metabolism immune function in vivo innovation insight insulin secretion islet metabolic phenotype novel pollutant preservation prevent restoration selenium deficiency selenocysteine insertion sequence binding protein 2 selenoprotein stress activated protein kinase tool translation factor

项目摘要

PROJECT SUMMARY/ABSTRACT Projected to afflict 642 million individuals globally by 2040, diabetes is a devastating metabolic disease that is increasingly tied to environmental toxicants. One such pollutant of immense public health significance is arsenic, which contaminates the drinking water for over 100 million individuals globally, including many living in the United States. Epidemiological evidence links arsenic exposure with diabetes; however, the mechanisms by which arsenic increases diabetes risk and the factors that modulate this risk remain incompletely known. Interestingly, arsenic and the essential element selenium have been known to have opposing biological functions for nearly 80 years. Selenium is incorporated into 25 unique proteins, selenoproteins, involved in cellular processes such as immune function, cell division, thyroid hormone metabolism, and redox handling. Built upon strengthening evidence that insulin-secreting pancreatic β-cells are a primary target of arsenic's metabolic toxicity and our preliminary studies demonstrating that selenoprotein deficiency augments arsenic's adverse effects on glucose metabolism, we propose the following central hypothesis: selenoproteins play an essential role in preserving glucose homeostasis by protecting insulin-secreting pancreatic β-cells from arsenic-induced dysfunction. To address this hypothesis, in Specific Aim 1 we will employ a novel β- cell-specific knockout of selenoproteins to examine the impact of this tissue-specific alteration on whole-body energy physiology as well as pancreatic islet architecture. To understand how reducing exposure to arsenic impacts diabetes risk, in Specific Aim 2 we will interrogate the conjecture that selenoproteins are required for recovery from arsenic-induced impairments in glucose metabolism; moreover, we will employ synchrotron X- ray fluorescence microscopy to perform tissue-level mapping of arsenic and selenium in pancreatic tissue to test the hypothesis that selenoproteins promote metabolic recovery by protecting pancreatic islets from arsenic accumulation and facilitating its clearance. In Specific Aim 3 we will expand upon our in vivo and cell line data to define the cellular defects in β-cell physiology induced by arsenic that are exacerbated by selenoprotein deficiency. In particular, we will focus on aspects of cellular physiology for which evidence suggests arsenic and selenium/selenoproteins have opposing actions, namely oxidative stress, AMP-activated protein kinase activity, and ATP generation. Furthermore, this aim will narrow in on a specific selenoprotein implicated in diabetes risk, glutathione peroxidase 1 (GPx1), to determine how this enzyme impacts arsenic-induced β-cell dysfunction and to ascertain whether common allelic variations in GPx1 account for differential sensitivity to arsenic-induced diabetes risk in humans. Collectively, the proposed studies will provide new knowledge regarding the essential role of selenoproteins in resisting arsenic-induced disruptions in glucose homeostasis, including identification of populations at heightened risk due to coexisting selenium deficiency and endemic arsenic exposure as well as those with polymorphisms in selenoproteins that enhance arsenic sensitivity.

项目总结/摘要预计到2040年，全球将有6.42亿人患糖尿病，糖尿病是一种毁灭性的代谢疾病，与环境毒物的联系越来越紧密其中一种对公众健康具有重大意义的污染物是砷污染了全球1亿多人的饮用水，其中包括许多生活在美国的流行病学证据将砷暴露与糖尿病联系起来;然而，砷增加糖尿病风险的机制和调节这种风险的因素仍然不完全清楚。有趣的是，已知砷和必需元素硒具有相反的生物学效应。运行近80年。硒被整合到25种独特的蛋白质中，硒蛋白，免疫功能、细胞分裂、甲状腺激素代谢和氧化还原处理等细胞过程。建立在强化证据的基础上，即分泌胰岛素的胰腺β细胞是砷的主要靶点。代谢毒性和我们的初步研究表明，硒蛋白缺乏增加砷的对葡萄糖代谢的不利影响，我们提出以下中心假设：硒蛋白发挥作用通过保护分泌胰岛素的胰腺β细胞在维持葡萄糖稳态中发挥重要作用砷引起的功能障碍为了解决这个假设，在具体目标1中，我们将采用一种新的β- 硒蛋白的细胞特异性敲除，以检查这种组织特异性改变对全身的影响能量生理学以及胰岛结构。为了了解减少砷暴露影响糖尿病风险，在具体目标2中，我们将询问硒蛋白是糖尿病风险所必需的推测。从砷引起的葡萄糖代谢损伤中恢复;此外，我们将采用同步加速器X-射线，射线荧光显微镜进行胰腺组织中砷和硒的组织水平映射，检验硒蛋白通过保护胰岛免受砷的侵害而促进代谢恢复的假设积累并促进其清除。在具体目标3中，我们将扩展我们的体内和细胞系数据确定砷诱导的β细胞生理学中的细胞缺陷，硒蛋白加剧了这些缺陷缺陷特别是，我们将集中在细胞生理学方面的证据表明，砷硒/硒蛋白具有相反的作用，即氧化应激、AMP激活的蛋白激酶活性和ATP生成。此外，这一目标将缩小在一个特定的硒蛋白牵连，糖尿病风险，谷胱甘肽过氧化物酶1（GPx 1），以确定这种酶如何影响砷诱导的β细胞功能障碍，并确定是否在GPx 1常见的等位基因变异解释不同的敏感性，砷引起的人类糖尿病风险。总的来说，拟议的研究将提供新的知识，关于硒蛋白在抵抗砷诱导的葡萄糖稳态破坏中的重要作用，包括查明由于硒缺乏和地方病共存而处于高度危险的人群砷暴露，以及那些在硒蛋白多态性，提高砷的敏感性。