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

低剂量砷影响支气管上皮细胞的先天免疫反应

• 批准号: 8832204
• 负责人: Britton C Goodale
• 金额: $ 5.24万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832204
• 关键词: Address; Adverse effects; Affect; Animals; Arsenic; Arsenicals; Asia; Bacteria; Bacterial Infections; Binding; Bioinformatics; Biological; Biological Assay; Biological Process; Blood; Bronchiectasis; Cacodylic Acid; Carcinogens; Cells; Chronic Obstructive Airway Disease; Data; Development; Dose; Environmental Pollution; Enzymes; Epithelial Cells; Exhibits; Exposure to; Fellowship; Food; Food Safety; Fruit; Gene Expression; Genes; Goals; Guidelines; Health; Heart Diseases; Human; Immune; Immune response; Infectious Lung Disorder; Investigation; Juice; Laboratories; Lead; Luciferases; Lung; Lung diseases; Messenger RNA; Metabolism; Methods; MicroRNAs; Molecular; Mononuclear; Morbidity - disease rate; Neurologic; Pathway interactions; Peptides; Pneumonia; Population; Production; Pulmonary Tuberculosis; RNA Binding; Recruitment Activity; Relative (related person); Reporter; Research; Research Training; Respiratory Tract Infections; Rice; Risk; Signal Pathway; Signaling Pathway Gene; Source; South America; System; Techniques; Testing; Training; Translations; Untranslated RNA; Validation; Virus; Virus Diseases; Vitamin D; Vitamin D3 Receptor; Water; Western Blotting; antimicrobial; antimicrobial peptide; base; bead chip; biological systems; cathelicidin; cathelicidin antimicrobial peptide; defense response; differential expression; drinking water; environmental chemical; inhibitor/antagonist; mRNA Expression; monomethylarsonous acid; mortality; nano-string; neutrophil; novel; pleiotropism; public health relevance; reproductive; research study; response

 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.

 描述（由申请人提供）：砷是一种环境化学品，由于其广泛存在于饮用水中及其对人类健康的多效性影响，因此备受关注。在亚洲和南美洲流行的高浓度砷是一种致癌物质，会导致发育、生殖、神经和心脏疾病，并增加传染性肺病的发病率和死亡率。在美国，约有2500万人暴露于超过EPA饮用水标准10 ppb的井水中的砷，最近的研究还发现大米，大米产品和果汁是有机砷暴露的重要来源。由于对生物效应知之甚少 低剂量砷暴露，我的研究的目标是测试的假设，无机和有机形式的砷在相关的美国人口的水平对人类支气管上皮细胞（HBE）的先天免疫反应产生不利影响。在初步实验中，我使用生物信息学方法来识别受环境相关暴露于二甲基胂酸（DMA）影响的基因和信号通路，DMA是一种存在于大米和大米产品中的有机砷形式，是人体血液中检测到的砷的主要形式。对HBE细胞中的总体mRNA和microRNA表达的分析显示，DMA诱导了两种microRNA的表达，这两种microRNA靶向维生素D代谢和抗菌肽凯萨林菌素（抗菌防御反应的重要组成部分）产生的关键信号通路。我的博士后研究训练将使我准备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来测试这些假设。因此，我将在两个具体目标中研究总体研究假设。在目标1中，我将使用生物信息学的方法来识别受低剂量一甲基亚胂酸（MMA）和无机砷（iAs）影响的生物过程，并比较砷暴露破坏的生物网络。在目标2中，我将研究来自我的初步生物信息学分析的假设，即DMA破坏了维生素D代谢和抗菌肽凯萨林菌素生产的关键信号通路。通过这项奖学金的研究培训将扩大我使用生物信息学方法来发现受砷影响的新途径的能力，并将提供新的数据，解决砷如何影响先天免疫途径的水平与美国相关。这些数据将为FDA考虑食品中有机和无机砷的指导方针提供相关和及时的信息。