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：
10091436
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 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091436
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 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.

项目概要/摘要预计到 2040 年，糖尿病将影响全球 6.42 亿人，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，这种具有巨大公共卫生意义的污染物是。砷，污染了全球超过 1 亿人的饮用水，其中包括许多生活在然而，美国的流行病学证据表明砷暴露与糖尿病有关；砷会增加糖尿病风险，而调节这种风险的因素仍不完全清楚。已知砷和必需元素硒具有相反的生物作用近 80 年来，硒被纳入 25 种独特的蛋白质（硒蛋白）中，参与细胞过程，如免疫功能、细胞分裂、甲状腺激素代谢和氧化还原处理。加强证据表明分泌胰岛素的胰腺 β 细胞是砷的主要目标代谢毒性和我们的初步研究表明，硒蛋白缺乏会增加砷的毒性对糖代谢的不利影响，我们提出以下中心假设：硒蛋白发挥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为了解决这一假设，在具体目标 1 中，我们将采用一种新型 β-。细胞特异性敲除硒蛋白，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了解如何减少砷暴露。影响糖尿病风险，在具体目标 2 中，我们将质疑硒蛋白是必需的猜想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- 射线荧光显微镜对胰腺组织中的砷和硒进行组织水平绘图检验硒蛋白通过保护胰岛免受砷侵害来促进代谢恢复的假设在具体目标 3 中，我们将扩展我们的体内和细胞系数据。确定砷引起的 β 细胞生理学细胞缺陷，并因硒蛋白而加剧特别是，我们将重点关注有证据表明砷存在的细胞生理学方面。硒/硒蛋白具有相反的作用，即氧化应激、AMP激活的蛋白激酶此外，这一目标将集中在与此相关的特定硒蛋白上。糖尿病风险，谷胱甘肽过氧化物酶 1 (GPx1)，以确定该酶如何影响砷诱导的 β 细胞功能障碍并确定 GPx1 中常见的等位基因变异是否解释了对总的来说，拟议的研究将提供新的知识。关于硒蛋白在抵抗砷引起的葡萄糖稳态破坏中的重要作用，包括识别因缺硒和地方病共存而面临胃肠道风险的人群砷暴露以及具有增强砷敏感性的硒蛋白多态性。