Arsenic Exposure, ER stress and Type 2 Diabetes

描述（由申请人提供）：环境砷污染对公众健康构成重大威胁，影响美国和全球超过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，但这种联系的分子和遗传机制仍然知之甚少。在细胞水平上，砷诱导适应性变化，称为ER（内质网）应激反应。ER应激反应与胰岛素失调和葡萄糖稳态受损密切相关，而胰岛素失调和葡萄糖稳态受损是T2 DM的关键标志。该项目的首要假设是砷暴露通过诱导细胞ER应激反应引起糖尿病。为了验证这一假设并阐明砷诱导ER应激的分子和遗传机制，我们提出了一项多学科研究，具体目标如下：1）进行全基因组功能遗传筛选，以发现关键参与砷诱导的ER应激的基因和遗传途径的综合图谱，2）检验砷影响葡萄糖稳态的假设（即胰腺β细胞中的胰岛素产生和脂肪细胞中的葡萄糖利用），和3）鉴定砷特异性ER应激基因中的遗传变异并评估它们与人群中T2 DM的关联。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影响的认识。这项研究将进一步加强广泛存在的环境毒素污染物（砷）与T2 DM（一种日益流行和毁灭性的人类疾病）之间的联系。从这项研究中获得的机制见解最终可能会带来更好的策略，用于诊断、预防和缓解环境中砷暴露引起的T2 DM。此外，我们对ER应激反应的研究将有助于了解其他人类疾病，其中病因在于基因-环境相互作用，导致细胞应激和适应性反应。

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.