Project 1: Molecular Drivers of Arsenic- Induced Diabetes

项目1：砷诱发糖尿病的分子驱动因素

• 批准号: 10570864
• 负责人: Praveen Sethupathy
• 金额: $ 32.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-20 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570864
• 关键词: 3' Untranslated Regions; Address; Affect; Archives; Arsenic; Beta Cell; Biological Assay; Biological Markers; Carcinogens; Cell Line; Cell Survival; Cells; Chromatin; Chronic; Collaborations; Complex; Data; Defect; Diabetes Mellitus; Disease; Environmental Exposure; Environmental Risk Factor; Etiology; Exposure to; Food; Functional disorder; Future; Genes; Genetic; Genetic Transcription; Goals; High-Throughput Nucleotide Sequencing; Human; Impairment; In Vitro; Insulin Resistance; Intervention; Intestines; Investigation; Islets of Langerhans; Knockout Mice; Knowledge; Laboratories; Link; Liver; Measures; Metabolic; Metabolic Diseases; Metabolic dysfunction; Methods; Methylation; MicroRNAs; Modeling; Molecular; Molecular Target; Mus; National Toxicology Program; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Persons; Phenotype; Plasma; Population Study; Prevalence; Privatization; Productivity; Public Health; Publishing; RNA; Reporter Genes; Reporting; Research; Role; Running; Sampling; Signal Recognition Particle; Small RNA; Structure of beta Cell of islet; Superfund; System; Techniques; Testing; Tissues; Toxicology; Transcriptional Regulation; Transfer RNA; Untranslated RNA; Vision; Water; bioinformatics pipeline; cohort; comorbidity; crosslinking and immunoprecipitation sequencing; diabetes risk; diabetic; diabetogen; diabetogenic; disease phenotype; disorder prevention; drinking water; experimental study; exposed human population; extracellular vesicles; gain of function; in vivo; inhibitor; insulin secretion; insulin signaling; islet; locked nucleic acid; loss of function; microbiome composition; mouse model; novel; novel therapeutics; overexpression; programs; superfund site; targeted treatment; transcription factor; transcriptome sequencing

ABSTRACT: PROJECT 1 Project 1 is highly integrated with the other projects in this SRP proposal, and the primary goal is directly in line with the theme of the center, “Identifying novel methods to reduce iAs exposure and elucidating mechanisms underlying iAs-induced metabolic dysfunction with a vision for disease prevention.” The project addresses the important public health issue of diabetes associated with environmental exposure to inorganic arsenic (iAs). It focuses on liver and pancreatic beta cell microRNAs (miRNAs) and transcription factors (TFs) as potential mechanisms of iAs-associated diabetes. The project co-leaders are Drs. Sethupathy and Styblo, experts in miRNA function and iAs toxicology. iAs has been highlighted as a diabetogen by the National Toxicology Program (NTP) 2012 review. Diabetes is a complex disorder that affects hundreds of millions of people worldwide, has no cure, is associated with numerous debilitating co-morbidities, and is a growing public health concern. Chronic exposure to iAs is a global problem as over 100 million people around the world (~13 million in US) drink water with unsafe levels of iAs and many more are exposed to iAs in food. Our prior research has shown that exposure to iAs is associated with increased prevalence of diabetes, and that impaired insulin secretion by pancreatic beta cells or impaired insulin signaling (insulin resistance) may underlie the diabetogenic effects of iAs. However, the mechanistic underpinnings of these effects are unknown. This proposal builds upon a productive collaboration between Drs. Sethupathy and Styblo and is based on robust preliminary data that points to miRNAs and TFs as strong candidate mechanistic links between iAs and diabetes. Over the last decade, specific miRNAs and TFs have independently emerged as markers of iAs exposure and as potential regulators of diabetes pathways. iAs exposure has been associated with significant changes in the levels of miRNAs and TFs in different tissues and cell lines. Importantly, some of these miRNAs and TFs have also been linked to diabetes in separate studies. Despite such intriguing findings, the relationship between iAs-exposure and miRNAs or TFs in diabetes has never been formally investigated. The goal of this study is to bridge this knowledge gap. Our central hypothesis is that specific miRNAs and TFs drive the diabetes phenotypes associated with iAs exposure, and that manipulation of these miRNAs and TFs will rescue these phenotypes. We will test this hypothesis through the use of in vitro cell-based systems, in vivo mouse models, and human samples. Given the potential for exposure to iAs and the public health issue of diabetes, understanding the complex relationships between environmental risk factors for diabetes is of critical importance.

摘要：项目1 项目1与该SRP提案中的其他项目高度融合，主要目标是直接的 以中心的主题，“识别新的方法来减少IAS暴露和阐明机制 IAS引起的基本代谢功能障碍具有预防疾病的愿景。”该项目解决了该项目 与环境暴露于无机砷（IAS）有关的糖尿病的重要公共卫生问题。 专注于肝脏和胰腺β细胞microRNA（miRNA）和转录因子（TFS） IAS相关糖尿病的机制。项目共同领导者是Drs。 Sethupathy和Styblo，专家 miRNA功能和IAS毒理学。国际IAS已被国家毒理学强调为糖尿病 计划（NTP）2012评论。糖尿病是一种复杂的疾病，影响数亿人 在世界范围内，无法治愈，与众多令人衰弱的合并症有关，并且正在不断增长的公共卫生 忧虑。长期接触IAS是一个全球问题，全球超过1亿人（约1300万人） 在美国）喝具有不安全水平的水的水，还有更多的食物中的IAS。我们先前的研究已经 表明暴露于IAS与糖尿病患病率的增加有关，并且胰岛素受损 胰腺β细胞的分泌或受损的胰岛素信号传导（胰岛素抵抗）可能是糖尿病基础的基础 IAS的影响。但是，这些作用的机械基础尚不清楚。该提议建立在 Drs之间的富有成效的合作。 Sethupathy和Styblo，基于强大的初步数据 将miRNA和TF指定为IAS和糖尿病之间的牢固候选机械联系。最后 十年，特定的miRNA和TF已独立出现为IAS暴露的标记，并且潜在 糖尿病途径的调节剂。 IAS暴露与水平的重大变化有关 不同组织和细胞系中的miRNA和TF。重要的是，其中一些miRNA和TF也是 在单独的研究中与糖尿病有关。尽管发现了如此有趣的发现，但IAS暴露之间的关系 糖尿病中的miRNA或TFS从未正式研究。这项研究的目的是桥接 知识差距。我们的中心假设是特定的miRNA和TFS驱动糖尿病表型 与IAS暴露有关，对这些miRNA和TF的操纵将为这些 表型。我们将通过使用基于体外细胞的系统（体内小鼠模型）来检验该假设 和人类样品。考虑到暴露于IAS和糖尿病的公共卫生问题的潜力， 了解糖尿病环境风险因素之间的复杂关系至关重要。