Environmental Arsenic and Diabetes Mellitus

环境砷与糖尿病

• 批准号: 8037454
• 负责人: Miroslav Styblo
• 金额: $ 30.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-07 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037454
• 关键词: Adipocytes; Adverse effects; Affect; Animals; Area; Arsenic; Arsenicals; Arts; Biochemical Genetics; Biological Markers; Blood; Cancerous; Cell Culture Techniques; Cells; Charge; Chronic; Cohort Studies; DNA Methylation; Data; Detection; Development; Diabetes Mellitus; Diet; Diet Habits; Disease; Environmental Carcinogens; Epigenetic Process; Etiology; Exposure to; Fingerprint; Funding; Gene Cluster; Genes; Genetic Polymorphism; Glucose; Goals; Health Sciences; Human; Individual; Institutes; Insulin; Insulin Antagonists; Laboratories; Laboratory Study; Lead; Link; Lymphocyte; Metabolic Pathway; Metabolism; Methylation; Mexican; Mexico; Molecular; Mus; North Carolina; Pattern; Population Study; Predisposition; Prevention; Research; Research Personnel; Risk; Risk Assessment; Signal Transduction; Signal Transduction Pathway; Sulfur; Systems Biology; Techniques; Tissues; Toxic effect; Translational Research; Urine; Urothelial Cell; Urothelium; Work; cohort; data integration; design; diabetes risk; dosimetry; drinking water; epigenomics; feeding; genome-wide; glucose uptake; innovation; metabolomics; novel; oxidation; parent project; translational approach; urinary

DESCRIPTION (provided by applicant): This ViCTER is built around the currently funded project 'Environmental Arsenic and Diabetes Mellitus' (R01 ES015326-01A2, PI: Miroslav Styblo). The current R01 project (further referred to as the parent project) uses a translational approach to characterize the association between chronic exposures to arsenic (As) and diabetes mellitus. The main goals of the parent project are: (1) to identify molecular mechanisms underlying the diabetogenic effects of inorganic As (iAs), (2) to identify specific metabolites of iAs that are responsible for these effects, and (3) to characterize genetic polymorphisms and dietary habits that are associated with increased susceptibility of individuals to iAs-induced diabetes. The proposed ViCTER will expand the scope of the parent project to include a comprehensive assessment of metabolomic and epigenomic profiles associated with iAs exposure and with iAs-induced disease. The primary objectives are: (1) to examine a complete As metabolome (arsenome) in urine of mice and humans who develop diabetes as a result of exposure to iAs; (2) to characterize tissue dosimetry for key metabolites of iAs, using exfoliated human urothelial cells; (3) to identify DNA methylation, and (4) to identify general metabolomic profiles associated with iAs exposure and with iAs-induced diabetes. Results of this work will provide novel information about the metabolomic and epigenetic fingerprints that characterize both the exposure to iAs and the iAs-induced diabetes. Integration of data from mouse and human studies will help to identify specific methylation profiles for genes and gene clusters affected by iAs exposure, and the signaling and metabolic pathways associated with these gene clusters. Using data on urinary arsenome and on the metabolites of iAs in exfoliated urothelial cells (and in mouse tissues analyzed in the parent project), we will be able to identify specific As species that are responsible for the iAs-induced changes on the epigenome and metabolome levels. The proposed research will lead to a better understanding of the mechanisms underlying the adverse effects of iAs exposures and aid in the establishment of novel biomarkers to identify individuals at greatest risk for arsenic-induced diabetes in an understudied region in Mexico and in the arsenicosis-endemic areas worldwide.

描述（由申请人提供）：此Victer围绕着当前资助的项目“环境砷和糖尿病”（R01 ES015326-01A2，PI：Miroslav Styblo）。当前的R01项目（进一步称为父项目）使用一种翻译方法来表征慢性暴露与砷（AS）和糖尿病之间的关联。父母项目的主要目标是：（1）确定无机糖尿病作用为（IAS）的分子机制（IAS），（2）确定对这些效果负责的特定IAS代谢产物，以及（3）表征遗传多态性和饮食习惯，这些疾病和饮食习惯与对个体对疾病的易感性增加有关。拟议的Victer将扩大父项目的范围，包括对与IAS暴露以及与IAS诱发的疾病相关的代谢组和表观基因组概况的全面评估。主要目标是：（1）在小鼠和人类尿液中检查完整的代谢组（砷），这些小鼠和人类因暴露于IAS而患上糖尿病； （2）使用去角质的人尿路上皮细胞来表征IAS关键代谢物的组织剂量法； （3）鉴定DNA甲基化，（4）确定与IAS暴露和IAS诱导的糖尿病相关的一般代谢组分。这项工作的结果将提供有关代谢组和表观遗传指纹的新信息，这些指纹既表征了IAS暴露和IAS诱导的糖尿病。来自小鼠和人类研究的数据的整合将有助于确定受IAS暴露影响的基因和基因簇的特定甲基化谱，以及与这些基因簇相关的信号传导和代谢途径。使用尿砷和IAS代谢产物的数据（在父母项目中分析的小鼠组织中）中，我们将能够将特定识别为负责IAS诱导的表观遗传组和代谢组水平变化的物种。拟议的研究将使人们更好地了解IAS暴露的不利影响的机制，并有助于建立新型的生物标志物，以识别墨西哥和全球砷中毒领域中砷诱发的糖尿病最大风险的个体。