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.

项目摘要/摘要预计到2040年，全球6.42亿个人受伤，糖尿病是一种毁灭性的代谢疾病与环境有毒物质相关。如此巨大的公共卫生意义的一种这样的污染物是砷在全球范围内污染了超过1亿人的饮用水，其中包括许多居住在美国。流行病学证据将砷暴露与糖尿病联系起来；但是，机制砷增加糖尿病风险和调节这种风险的因素尚不完全了解。有趣的是，众所周知，砷和基本元素具有相反的生物学功能将近80年。硒掺入25种独特的蛋白质，硒蛋白，涉及细胞过程，例如免疫功能，细胞分裂，甲状腺马酮代谢和氧化还原处理。建立在加强证据表明胰岛素分泌胰腺β细胞的基础上是砷的主要目标代谢毒性和我们的初步研究表明，硒蛋白缺乏症增加了砷对葡萄糖代谢的不利影响，我们提出以下中心假设：硒蛋白的发挥通过保护胰岛素分泌胰腺β细胞来保存葡萄糖稳态的重要作用来自砷引起的功能障碍。为了解决这一假设，在特定的目标1中，我们将采用一种新型的β- 硒蛋白的细胞特异性敲除检查该组织特异性改变对全身的影响能量生理以及胰岛建筑。了解如何减少对砷的接触影响糖尿病的风险，在特定目的2中，我们将询问硒蛋白需要的猜想从砷诱导的葡萄糖代谢损伤中恢复；此外，我们将采用同步加速器x- 射线荧光显微镜以执行胰腺组织中砷和硒的组织水平映射到检验硒蛋白通过保护胰岛免受砷而促进代谢恢复的假设积累并支持其清除率。在特定目标3中，我们将扩展我们的体内和细胞系数据定义砷诱导的β细胞生理学中的细胞缺陷，这些缺陷被硒蛋白加剧了不足。特别是，我们将重点关注细胞生理的方面，证据表明砷硒/硒蛋白具有相反的作用，即氧化应激，AMP激活的蛋白激酶活动和ATP生成。此外，该目标将缩小在实施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化是否解释了对砷引起的糖尿病风险。拟议的研究集体将提供新的知识关于硒蛋白在抵抗砷诱导的葡萄糖稳态中的破坏中的重要作用，包括识别由于硒缺陷和内部人群共存的风险增加的人群砷暴露以及硒蛋白中具有多态性的砷暴露，从而增强砷敏感性。