权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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/文摘