Project 1: Molecular Drivers of Arsenic- Induced Diabetes

摘要：项目1 项目1与本SRP建议书中的其他项目高度整合，主要目标与 该中心的主题是“确定减少iAs暴露的新方法并阐明机制”。 潜在的iAs诱导的代谢功能障碍与疾病预防的愿景。该项目解决了 糖尿病与无机砷环境暴露相关的重要公共卫生问题。它 重点关注肝脏和胰腺β细胞microRNAs（miRNAs）和转录因子（TF）， iAs相关糖尿病的机制。该项目的共同领导人是Sethupathy和Styblo博士，他们是 miRNA功能和iAs毒理学。iAs已被国家毒理学强调为糖尿病原 计划（NTP）2012年审查。糖尿病是一种影响数亿人的复杂疾病 在世界范围内，没有治愈方法，与许多使人衰弱的合并症有关，并且是一种日益严重的公共卫生问题。 关心长期暴露于iAs是一个全球性问题，全世界有1亿多人（约1300万 在美国）饮用水中含有不安全水平的iAs，更多的人暴露于食物中的iAs。我们之前的研究 表明iAs暴露与糖尿病患病率增加有关， 胰腺β细胞的分泌或受损的胰岛素信号传导（胰岛素抵抗）可能是糖尿病发生的基础。 iAs的影响。然而，这些影响的机制基础是未知的。该提案基于 Sethupathy博士和Styblo博士之间富有成效的合作，并基于强大的初步数据， 指出miRNA和TF是iAs和糖尿病之间强有力的候选机制联系。在过去 十年来，特异性miRNA和TF已经独立地作为iAs暴露的标志物和潜在的 糖尿病通路的调节剂。iAs暴露与以下水平的显著变化有关： 不同组织和细胞系中的miRNA和TF。重要的是，这些miRNAs和TF中的一些也被发现。 与糖尿病有关。尽管有这些有趣的发现，iAs暴露之间的关系 而糖尿病中的miRNAs或TF从未被正式研究过。这项研究的目的是弥合这一点， 知识差距。我们的中心假设是特定的miRNAs和TF驱动糖尿病表型 与iAs暴露相关，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，体内小鼠模型， 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， 了解糖尿病环境危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.