Low-dose arsenic impacts innate immune response in bronchial epithelial cells

 说明(申请人提供)：砷是一种非常令人关注的环境化学物质，因为它广泛存在于饮用水中，并对人类健康具有多效性。在高浓度下，砷是亚洲和南美洲的地方病，是一种致癌物质，会导致发育、生殖、神经和心脏疾病，并增加传染性肺部疾病的发病率和死亡率。在美国，约有2500万人暴露在超过美国环保局饮用水标准10 ppb的井水中，最近的研究还发现，大米、稻米制品和果汁是有机砷暴露的重要来源。由于人们对这种生物效应知之甚少 对于低剂量砷暴露，我研究的目标是验证这样一种假设，即与美国人口相关的水平的无机和有机形式的砷对人类支气管上皮(HBE)细胞的天然免疫反应产生不利影响。在初步实验中，我使用生物信息学的方法来识别与环境相关的接触二甲基砷酸(DMA)影响的基因和信号通路。二甲基砷酸是一种有机形式的砷，存在于大米和大米产品中，也是在人类血液中检测到的主要形式的砷。对HBE细胞中全局mRNA和microRNA表达的分析表明，DMA诱导了两个microRNAs的表达，这两个microRNAs的目标是维生素D代谢和抗菌素(抗菌防御反应的重要组成部分)的产生的关键信号通路。我的博士后研究培训将使我准备好使用各种生物信息学技术来确定其他新的研究途径，并在实验室中使用分子方法测试这些假说。因此，我将从两个具体的目标来研究这个最重要的研究假设。在目标1中，我将使用生物信息学方法来确定受低剂量单甲基亚砷酸(MMA)和无机砷(IAS)影响的生物过程，并比较受砷暴露破坏的生物网络。在目标2中，我将调查根据我的初步生物信息学分析得出的假设，即DMA扰乱了对维生素D新陈代谢和抗菌素产生至关重要的信号通路。通过该奖学金进行的研究培训将扩大我使用生物信息学方法发现受砷影响的新途径的能力，并将提供新的数据，说明砷如何在与美国相关的水平上影响先天免疫途径。这些数据将在FDA考虑食品中有机和无机砷的指导方针时提供相关和及时的信息。

 DESCRIPTION (provided by applicant): Arsenic is an environmental chemical of great concern because of its widespread presence in drinking water and its pleiotropic effects on human health. At high concentrations, which are endemic to Asia and South America, arsenic is a carcinogen, causes developmental, reproductive, neurological, and cardiac disease, and increases morbidity and mortality from infectious lung diseases. In the US, ~25 million people are exposed to arsenic in well water that exceeds the EPA drinking water standard of 10 ppb, and recent studies have additionally identified rice, rice based products and fruit juices as significant sources of organic arsenic exposure. Since little is known about the biological effects low-dose arsenic exposure, the goal of my research is to test the hypothesis that inorganic and organic forms of arsenic at levels relevant to the US population adversely affect the innate immune response in human bronchial epithelial (HBE) cells. In preliminary experiments, I used a bioinformatic approach to identify genes and signaling pathways that were affected by environmentally-relevant exposure to dimethylarsinic acid (DMA), an organic form of arsenic that is present in rice and rice-based products, and is the predominant form of arsenic detected in human blood. Analysis of global mRNA and microRNA expression in HBE cells revealed that DMA induced the expression of two microRNAs that target a signaling pathway critical for vitamin D metabolism and production of the antimicrobial peptide cathelicidin, an important component of the antimicrobial defense response. My postdoctoral research training will prepare me to identify additional novel research avenues using a variety of bioinformatic techniques, and to test these hypotheses using molecular methods in the laboratory. Thus, I will investigate the overarching research hypothesis in two specific aims. In Aim 1, I will use a bioinformatic approach to identify biological processes affected by low-dose monomethylarsonous acid (MMA) and inorganic arsenic (iAs), and to compare biological networks disrupted by arsenic exposures. In Aim 2, I will investigate the hypothesis, derived from my preliminary bioinformatic analysis, that DMA disrupts a signaling pathway critical for vitamin D metabolism, and production of the antimicrobial peptide cathelicidin. Research training through this fellowship will expand my ability to use bioinformatic approaches to discover novel pathways affected by arsenic, and will provide new data that addresses how arsenic affects innate immune pathways at levels relevant to the US. This data will provide relevant and timely information as the FDA considers guidelines for organic and inorganic arsenic in food.