Arsenic Exposure, ER stress and Type 2 Diabetes

描述(申请人提供)：环境砷污染对公众健康构成重大威胁，影响到美国和世界各地超过1.4亿人。流行病学研究表明，砷暴露与2型糖尿病(T2 DM)的发展之间存在联系，但这种联系背后的分子和遗传机制仍然知之甚少。在细胞水平上，砷诱导称为内质网(ER)应激反应的适应性变化。内质网应激反应与胰岛素失调和糖稳态受损密切相关，这些都是T2 DM的主要特征。该项目的主要假设是，砷暴露通过诱导细胞内质网应激反应而导致糖尿病。为了验证这一假说并阐明砷诱导内质网应激的分子和遗传学机制，我们提出了一项多学科的研究，具体目标如下：1)进行全基因组功能遗传筛选，以发现与砷诱导的内质网应激有关的基因和遗传途径的全面图谱；2)验证砷通过对内质网应激基因的功能调节而影响葡萄糖稳态(即胰岛β细胞的胰岛素产生和脂肪细胞对葡萄糖的利用)的假说；以及3)鉴定砷特异的内质网应激基因的遗传变异，并评估它们与人类T2 DM的关系。这项综合性和多学科的研究将促进我们对砷暴露的糖尿病致病作用的理解。这项研究将进一步加强一种广泛存在的环境毒素污染物(砷)与T2 DM之间的联系。T2 DM是一种日益流行的破坏性人类疾病。从这项研究中获得的机械性见解最终可能会导致更好的诊断、预防和缓解环境中砷暴露引起的T2 DM的策略。此外，我们对内质网应激反应的研究将有助于理解其他人类疾病，这些疾病的病因学存在于导致细胞应激和适应性反应的基因-环境相互作用。

DESCRIPTION (provided by applicant): Environmental arsenic contamination poses a major threat to public health, affecting over 140 million people in the US and worldwide. Epidemiological studies show a link between arsenic exposure and the development of type 2 diabetes mellitus (T2DM), yet the molecular and genetic mechanisms underlying this link remain poorly understood. At the cellular level, arsenic induces adaptive changes known as the ER (endoplasmic reticulum) stress response. The ER stress response is critically implicated in insulin dysregulation and impaired glucose homeostasis that are key hallmarks of T2DM. The overarching hypothesis of this project is that arsenic exposures cause diabetes by inducing the cellular ER stress response. To test this hypothesis and to elucidate the molecular and genetic mechanisms of arsenic-induced ER stress, we propose a multidisciplinary study with the following specific aims: 1) to perform genome-wide functional genetic screens to discover a comprehensive map of genes and genetic pathways that are critically involved in arsenic-induced ER stress, 2) to test the hypothesis that arsenic impacts glucose homeostasis (i.e. insulin production in pancreatic beta cells and glucose utilization in fat cells) through its functional modulation of ER stress genes, and 3) to identify genetic variants in the arsenic-specific ER stress genes and assess their association with T2DM in a human population. This integrative and multidisciplinary study will advance our understanding of the well-established yet poorly understood diabetogenic effects of arsenic exposure. The research will further strengthen the link between a widespread environmental toxin contaminant (arsenic) and T2DM--an increasingly prevalent and devastating human disease. Mechanistic insights gained from the study may ultimately lead to better strategies for the diagnosis, prevention and alleviation of T2DM caused by exposure to arsenic in the environment. Furthermore, our study on ER stress response will contribute to the understanding of other human diseases, in which etiology resides at gene-environment interactions that cause cellular stress and adaptive responses.