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（由应用提供）：砷是一种非常关注的环境化学物质，因为它在饮用水中的宽度及其对人类健康的多效影响。在高浓度的亚洲和南美，砷是一种致癌物，会引起发育，生殖，神经系统疾病，并增加感染性肺部疾病的发病率和死亡率。在美国，约有2500万人在井水中暴露于超过EPA饮用水标准为10 ppb的井中，并且最近的研究还确定了大米，水稻的产品和果汁是有机砷暴露的重要来源。由于对生物学效应知之甚少低剂量的砷暴露，我的研究的目的是检验以下假设：与美国人群相关的无机和有机形式的砷形式在人支气管上皮（HBE）细胞中对先天免疫反应产生不利影响。在初步实验中，我使用了生物信息学方法来鉴定受环境与环境相关的二甲基异丙胺酸（DMA）影响的基因和信号传导途径，DMA（DMA）是水稻和水稻产物中存在的有机砷形式，并且是人类血液中砷的主要形式。对HBE细胞中的全球mRNA和microRNA表达的分析表明，DMA诱导了两个microRNA的表达，这些microRNA靶向对维生素D代谢至关重要的信号传导途径以及抗菌胡椒cathelicidin的产生，这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准备使用各种生物信息学技术识别其他新型研究途径，并使用实验室中的分子方法检验这些假设。在AIM 1中，我将使用一种生物信息学方法来鉴定受低剂量单甲基酸（MMA）和无机砷（IAS）影响的生物学过程，并比较受砷暴露破坏的生物网络。在AIM 2中，我通过该奖学金进行研究培训将扩大我发现受砷影响的新型途径的能力，并将提供新的数据，以解决砷如何影响与美国相关的水平的先天免疫途径。随着FDA考虑食品中有机和无机砷的指南，这些数据将提供相关和及时的信息。