Arsenic related cystic fibrosis

项目总结/摘要 环境砷暴露与肺炎、支气管扩张和 糖尿病将砷暴露与肺病和糖尿病联系起来的潜在生化途径是 很难研究，但砷中毒的症状与囊性纤维化重叠，囊性纤维化是一种罕见的常染色体 最常见于北方欧洲血统的人的隐性疾病。越来越多的证据表明 砷中毒和囊性纤维化有一个共同的机制：囊性纤维化功能障碍， 跨膜调节因子（CFTR）。CFTR是一种氯离子通道，调节细胞内液体转运， 肺胰腺和其他器官细胞培养的研究表明，砷导致CFTR降解， 我们最近的流行病学研究表明，暴露于砷的人类也表现出CFTR功能障碍。 了解这些具体机制对于开发有效的预防和治疗药物至关重要。 干预措施。 在这项提案中，我们计划研究高砷暴露的成年人CFTR功能障碍是否有助于 肺功能减退和糖尿病我们提出了一套全面的研究，利用 孟加拉国农村地区的研究人群，这个国家目前正在经历一场流行病， 砷中毒是由受污染的饮用水引起的。我们假设砷的影响减少了 肺功能和糖尿病的风险通过诱导CFTR功能障碍。我们将使用已建立的生化 技术，包括汗液试验和外周血单个核细胞的Western Blot，以评估CFTR 功能在这个应用中，我们提出的初步数据表明，汗液氯化物，一种非侵入性的， 容易获得的测量结果，在高砷暴露的个体中升高。我们现在将测试 汗液氯化物浓度是否可用于识别低呼吸道疾病风险较高的个体 功能和糖尿病与砷暴露有关。我们的分析将采用因果中介分析， 研究与砷有关的疾病是否可归因于CFTR功能障碍。 这些研究探讨了砷可能增加肺部疾病和糖尿病风险的机制， 人类，并使用一个独特的人口与高砷暴露的成年人，以测试假设。我们 长期目标是开发新的筛查策略，以识别肺部疾病高危人群 和糖尿病由于环境暴露，并直接发展更有效的预防 干预措施。

PROJECT SUMMARY/ABSTRACT Environmental arsenic exposure is associated with increased rates of pneumonia, bronchiectasis, and diabetes. The underlying biochemical pathways that link arsenic exposure to lung disease and diabetes are difficult to study, but the symptoms of arsenic toxicity overlap with those of cystic fibrosis, a rare autosomal recessive disease most common in people of Northern European ancestry. Accumulating evidence suggests that arsenic toxicity and cystic fibrosis share a common mechanism: dysfunction of the cystic fibrosis transmembrane regulator (CFTR). CFTR is a chloride channel that regulates intracellular fluid transport in the lungs, pancreas, and other organs. Studies in cell culture show that arsenic causes degradation of CFTR, and our recent epidemiological study demonstrates that humans exposed to arsenic also exhibit CFTR dysfunction. It is critical to understand these specific mechanisms in order to develop effective preventive and therapeutic interventions. In this proposal, we plan to study whether CFTR dysfunction in adults with high arsenic exposure contributes to diminished lung function and diabetes. We propose a comprehensive set of studies that leverage an established study population in rural Bangladesh, a country that is currently experiencing an epidemic of arsenic poisoning through contaminated drinking water. We hypothesize that arsenic influences diminished lung function and risk of diabetes by inducing CFTR dysfunction. We will use established biochemical techniques, including sweat test and Western Blot of peripheral blood mononuclear cells, to assess CFTR function. In this application, we present preliminary data that suggest that sweat chloride, a noninvasive measure that is easy to obtain, is elevated among individuals with high arsenic exposure. We will now test whether sweat chloride concentration can be used to identify individuals at higher risk for low respiratory function and diabetes related to arsenic exposure. Our analyses will employ causal mediation analysis to investigate whether diseases related to arsenic can be attributed to CFTR dysfunction. These studies explore mechanisms by which arsenic may increase risk of lung disease and diabetes in humans, and use a unique population of adults with high arsenic exposure in order to test hypotheses. Our long-range goals are to develop novel screening strategies to identify populations at high risk for lung disease and diabetes due to environmental exposure, and to direct the development of more effective preventive interventions.