Project 1: Molecular Drivers of Arsenic- Induced Diabetes

摘要：项目1 项目1与本SRP提案中的其他项目高度集成，主要目标直接一致 该中心的主题是“确定减少IAS暴露的新方法和阐明机制” 潜在的IAS引起的代谢功能障碍，并着眼于疾病预防。该项目针对的是 与环境中无机砷暴露相关的糖尿病的重要公共卫生问题。它 重点关注肝脏和胰腺的β细胞微RNA(MiRNAs)和转录因子(TF)作为潜在的 IAS相关糖尿病的发病机制。该项目的联合负责人是Sthuparsis博士和Styblo博士，他们是 MiRNA功能与IAS毒理学。IAS已被国家毒理学委员会强调为糖尿病原 计划(NTP)2012年回顾。糖尿病是一种复杂的疾病，影响着数亿人 在世界范围内，它没有治愈方法，与许多令人衰弱的共病有关，是一个日益严重的公共卫生问题 担忧。长期接触IAS是一个全球性问题，因为世界各地有1亿多人(约1300万人) 在美国)饮用含有不安全水平的IAS的水，更多的人在食品中暴露于IAS。我们之前的研究已经 研究表明，暴露在IAS中与糖尿病患病率的增加有关，而胰岛素受损 胰岛β细胞分泌或胰岛素信号受损(胰岛素抵抗)可能是导致糖尿病的原因。 国际会计准则的影响。然而，这些效应的机制基础尚不清楚。这项建议的基础是 塞图帕西博士和Styblo博士之间富有成效的合作，基于强大的初步数据， 指出miRNAs和TF是IAS和糖尿病之间强有力的候选机制联系。在过去的几年里 十年来，特定的miRNAs和Tf已经独立地作为IAS暴露的标志和潜在的出现 糖尿病途径的调节者。暴露于IAS与以下物质水平的显著变化有关 不同组织和细胞系中的miRNAs和Tf。重要的是，其中一些miRNAs和TF也被 在单独的研究中发现与糖尿病有关。尽管有这些耐人寻味的发现，但IAS与暴露之间的关系 而糖尿病中的miRNAs或TF从未被正式研究过。这项研究的目标是在这两者之间架起一座桥梁 知识鸿沟。我们的中心假设是特定的miRNAs和TF驱动糖尿病表型 与IAS暴露有关，操纵这些miRNAs和TF将拯救这些 表型。我们将通过使用体外细胞系统、活体小鼠模型、 和人体样本。考虑到接触IAS的可能性和糖尿病的公共卫生问题， 了解糖尿病的环境风险因素之间的复杂关系至关重要。

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.