Arsenic related cystic fibrosis

项目摘要/摘要 环境砷暴露与肺炎、支气管扩张症和 糖尿病。将砷暴露与肺部疾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的症状重叠，囊性纤维化是一种罕见的常染色体 在北欧血统的人中最常见的隐性疾病。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 跨膜调节剂(CFTR)。CFTR是一种氯离子通道，调节细胞内液体的运输。 肺、胰腺和其他器官。在细胞培养中的研究表明，砷会导致CFTR的降解，并且 我们最近的流行病学研究表明，暴露在砷中的人类也表现出CFTR功能障碍。 了解这些具体的机制对于开发有效的预防和治疗是至关重要的。 干预措施。 在这项建议中，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 在孟加拉国农村建立了研究人口，这个国家目前正在经历一场艾滋病疫情 受污染的饮用水导致砷中毒。我们假设砷的影响会减弱 肺功能和通过诱导CFTR功能障碍患糖尿病的风险。我们将使用已建立的生化系统 包括汗液试验和外周血单核细胞Western Blot在内的技术评估CFTR 功能。在这项应用中，我们提供的初步数据表明，汗氯化物，一种非侵入性的 在高砷暴露的个体中，容易获得的指标会升高。我们现在要测试一下 是否可以用氯化汗液浓度来识别下呼吸道疾病的高危人群 与砷暴露相关的功能和糖尿病。我们的分析将采用因果调解分析来 调查与砷相关的疾病是否可以归因于CFTR功能障碍。 这些研究探索了砷可能增加人体内肺部疾病和糖尿病风险的机制。 并使用一组独特的高砷暴露成人人群来验证假设。我们的 长期目标是开发新的筛查策略来识别肺部疾病的高危人群 并对糖尿病因环境暴露而直接制定更有效的预防措施 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.