Arsenic and Innate Immunity in Human Lung

砷与人肺的先天免疫

• 批准号: 8881879
• 负责人: Bruce A. Stanton
• 金额: $ 0.12万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881879
• 关键词: Acids; Acute; Address; Adverse effects; Affect; American; Animal Model; Animals; Arsenic; Arsenites; Bacterial Infections; Biochemical; Bioinformatics; Biological; Blood; Bronchiectasis; Cardiovascular Diseases; Cause of Death; Chronic; Chronic Obstructive Airway Disease; Communities; Cystic Fibrosis; Cytokine Gene; Development; Diabetes Mellitus; Dose; Down-Regulation; Environmental Exposure; Epidemiologic Studies; Epithelial Cells; Exposure to; Food; Food Safety; Functional RNA; Gene Expression; Genes; Goals; Health; Human; IL8 gene; Immune; Immune response; Immune system; Infection; Inflammatory Response; Interleukin-6; Knowledge; Laboratories; Lead; Lung; Lung diseases; Malignant Neoplasms; Measures; Mercury; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Natural Immunity; Pathway interactions; Patients; Play; Pneumonia; Population; Post-Translational Regulation; Production; Pseudomonas; Pseudomonas aeruginosa; Relative (related person); Respiratory Tract Infections; Respiratory physiology; Rice; Risk; Role; Source; TNF gene; Testing; Virus Diseases; abstracting; base; cytokine; drinking water; early childhood; early life exposure; environmental chemical; in utero; inhibitor/antagonist; insight; mRNA Expression; macrophage; monomethylarsonic acid; mortality; novel; pathogen; protein expression; reproductive; response; tool; young adult

Project 3: Abstract Arsenic (As) is the number one environmental chemical of concern with regard to human health in the US. Epidemiological studies have shown that exposure to As increases lung disease, including pneumonia, and chronic obstructive pulmonary disease. In studies on experimental animals low levels of As inhibit the ability of the innate immune system to eliminate respiratory infections, and down regulate the expression of innate immune genes, but the molecular mechanisms whereby As inhibits the innate immune system is unknown. Moreover, the effects of inorganic versus organic As on the innate immune system is unknown. Accordingly, the goal of this application is to test the hypothesis that inorganic and organic forms have differential, dose dependent effects on the Pseudomonas aeruginosa (Pa) infections in the lung by adversely affecting the innate immune response. This will be investigated in two specific aims. Specific Aim #1 will test the hypothesis that arsenite, monomethylarsonic acid (MMA) and dimetheylarsinic acid (DMA) have differential, dose dependent effects on the secretion of proinflammatory cytokines by human bronchial epithelial (HBE) cells and macrophages in response to Pa. Studies will be conducted to examine the effects of arsenite, MMA and DMA, at levels relevant to the US population, on cytokine production by HBE cells and macrophages exposed to Pa. Specific Aim #2 will test the hypothesis that arsenite, MMA and DMA have differential, dose dependent effects on the expression of proinflammatory cytokine genes by HBE cells and macrophages in response to Pa by selectively regulating microRNA (miRNA) expression. Using advanced bioinformatic and molecular biological approaches, studies will be conducted to elucidate how miRNAs regulated by As modulate the inflammatory response to Pa. These studies will provide novel information regarding the dose and species dependent effects of arsenite, MMA and DMA, at levels relevant to the US population, on the immune response to Ps, a pathogen that causes significant morbidity and mortality in the US, as well as provide novel insight into the molecular mechanism(s) whereby As modulates the innate immune response of the human lung to Pa.

项目 3：摘要 砷 (As) 是美国对人类健康影响最大的环境化学物质。 流行病学研究表明，接触砷会增加肺部疾病，包括肺炎和 慢性阻塞性肺疾病。在对实验动物的研究中，低水平的砷会抑制 先天免疫系统消除呼吸道感染，并下调先天免疫系统的表达 免疫基因，但砷抑制先天免疫系统的分子机制尚不清楚。 此外，无机砷与有机砷对先天免疫系统的影响尚不清楚。因此， 该应用程序的目标是测试无机和有机形式具有差异、剂量的假设 通过对先天性的不利影响，对肺部铜绿假单胞菌 (Pa) 感染产生依赖性影响 免疫反应。我们将针对两个具体目标对此进行研究。具体目标 #1 将检验以下假设： 亚砷酸盐、一甲基胂酸 (MMA) 和二甲基胂酸 (DMA) 具有差异性、剂量依赖性 对人支气管上皮（HBE）细胞促炎细胞因子分泌的影响 巨噬细胞对 Pa 的反应。将进行研究以检查亚砷酸盐、MMA 和 DMA 的影响， 在与美国人口相关的水平上，暴露于 Pa 的 HBE 细胞和​​巨噬细胞产生细胞因子。 具体目标 #2 将检验亚砷酸盐、MMA 和 DMA 具有不同的、剂量依赖性效应的假设 对 HBE 细胞和​​巨噬细胞响应 Pa 促炎细胞因子基因表达的影响 选择性调节 microRNA (miRNA) 的表达。利用先进的生物信息学和分子生物学 方法，将进行研究以阐明 As 调节的 miRNA 如何调节炎症 这些研究将提供有关剂量和物种依赖性影响的新信息 亚砷酸盐、MMA 和 DMA 的含量与美国人口相关，对 Ps（一种病原体）的免疫反应 这在美国造成了显着的发病率和死亡率，并为分子生物学提供了新的见解 As 调节人肺对 Pa 的先天免疫反应的机制。