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

基本信息

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
项目类别：
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

项目摘要

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）：砷是一种备受关注的环境化学物质，因为它广泛存在于饮用水中，并且对人类健康具有多效性影响，砷在亚洲和南美洲普遍存在，在高浓度下是一种致癌物质，会导致癌症。在美国，约 2500 万人接触的井水中的砷超过了 EPA 饮用水标准。 10 ppb，最近的研究还发现大米、大米制品和果汁是有机砷暴露的重要来源，因为人们对其生物效应知之甚少。低剂量砷暴露，我的研究目标是检验以下假设：与美国人口相关的无机和有机形式的砷会对人类支气管上皮 (HBE) 细胞的先天免疫反应产生不利影响。使用生物信息学方法来识别受与环境相关的二甲基胂酸（DMA）接触影响的基因和信号传导途径，二甲基胂酸是一种有机形式的砷，存在于水稻和水稻中。对 HBE 细胞中整体 mRNA 和 microRNA 表达的分析表明，DMA 诱导了两种 microRNA 的表达，这些 microRNA 的目标是对维生素 D 代谢和生产至关重要的信号通路。抗菌肽抗菌素是抗菌防御反应的重要组成部分，我的博士后研究培训将使我能够利用各种生物信息技术确定其他新的研究途径，并利用分子方法测试这些假设。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方法来识别受低剂量单甲基胂酸 (MMA) 和无机砷 (iAs) 影响的生物过程。为了比较砷暴露对生物网络的破坏，我将研究根据我的初步生物信息分析得出的假设，即 DMA 会破坏对维生素 D 代谢至关重要的信号通路，通过该奖学金进行的研究培训将扩展我使用生物信息学方法发现砷影响的新途径的能力，并将提供新的数据来解决砷如何影响与美国相关的先天免疫途径。当 FDA 考虑食品中有机和无机砷的指导方针时，将提供相关和及时的信息。