In utero arsenic and H1N1 influenza- the role of CD8+ T cells in immunopathology

子宫内砷和 H1N1 流感 - CD8 T 细胞在免疫病理学中的作用

基本信息

批准号：
8071223
负责人：
Courtney D Kozul
金额：
$ 1.88万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2011-08-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071223
关键词：
Adult Adverse effects Affect Albumins Animal Model Antiviral Agents Antiviral Response Arsenic Avian Influenza Birth Body Weight decreased Brefeldin A Bronchiectasis Bronchoalveolar Lavage Fluid CD8B1 gene Cardiovascular Diseases Cells Cessation of life Chemicals Child Chile Chronic Chronic lung disease Contracts Data Defect Development Diabetes Mellitus Differential Threshold Disease Dose Environmental Exposure Environmental Health Epidemiology Etiology Exposure to Fertilization Flow Cytometry Functional disorder Geographic Locations Goals Health Histopathology Hospitalization Hour Human Immune System Diseases Immune System and Related Disorders Immune response Immune system In Situ Infection Influenza Influenza A Virus, H1N1 Subtype Ingestion Inhalation Exposure Investigation Lead Life Link Lung Lung diseases Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Measures Mexico Morbidity - disease rate Mothers Mus Nature Onset of illness Ovalbumin Oxygen Peptides Play Population Predisposition Production Public Health Recombinants Recurrence Research Residual state Respiratory Tract Infections Risk Risk Factors Role Route Severities Skin Cancer Source Southeastern Asia T cell response T-Cell Receptor T-Lymphocyte Testing Time Transgenic Organisms Viral Viral Antigens Virus Diseases Weaning base cytokine cytotoxic disorder risk drinking water early childhood early life exposure environmental agent exposed human population immunopathology in utero in vivo influenza outbreak interest lifetime risk lung injury mortality mouse model pandemic influenza postnatal public health relevance respiratory respiratory infection virus respiratory virus response standardize measure swine flu toxicant

Adult Adverse effects Affect Albumins Animal Model Antiviral Agents Antiviral Response Arsenic Avian Influenza Birth Body Weight decreased Brefeldin A Bronchiectasis Bronchoalveolar Lavage Fluid CD8B1 gene Cardiovascular Diseases Cells Cessation of life Chemicals Child Chile Chronic Chronic lung disease Contracts Data Defect Development Diabetes Mellitus Differential Threshold Disease Dose Environmental Exposure Environmental Health Epidemiology Etiology Exposure to Fertilization Flow Cytometry Functional disorder Geographic Locations Goals Health Histopathology Hospitalization Hour Human Immune System Diseases Immune System and Related Disorders Immune response Immune system In Situ Infection Influenza Influenza A Virus, H1N1 Subtype Ingestion Inhalation Exposure Investigation Lead Life Link Lung Lung diseases Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Measures Mexico Morbidity - disease rate Mothers Mus Nature Onset of illness Ovalbumin Oxygen Peptides Play Population Predisposition Production Public Health Recombinants Recurrence Research Residual state Respiratory Tract Infections Risk Risk Factors Role Route Severities Skin Cancer Source Southeastern Asia T cell response T-Cell Receptor T-Lymphocyte Testing Time Transgenic Organisms Viral Viral Antigens Virus Diseases Weaning base cytokine cytotoxic disorder risk drinking water early childhood early life exposure environmental agent exposed human population immunopathology in utero in vivo influenza outbreak interest lifetime risk lung injury mortality mouse model pandemic influenza postnatal public health relevance respiratory respiratory infection virus respiratory virus response standardize measure swine flu toxicant

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项目摘要

DESCRIPTION (provided by applicant): Chronic arsenic (As) exposure is considered the number one chemical of environmental health concern in the US and worldwide, and has been associated with increased risk of a wide variety of serious illnesses including various cancers, cardiovascular disease, diabetes, and other significant non-cancer disease risks. The primary route of exposure is through ingestion of drinking water that has been contaminated with inorganic As from natural geological sources. Epidemiological evidence from an As-exposed population in Chile demonstrated that in utero and early childhood exposure to As was associated with a 46-fold increase in the risk of death from bronchiectasis decades after cessation of exposure. The extraordinary magnitude and unexpected residual aspect of this risk warrants further investigation into the underlying mechanism and the connection between early life As exposure and adult disease. It is thought that recurrent respiratory infections play a major role in the development of bronchiectasis. In addition, respiratory infections by viruses such as influenza are a significant cause of morbidity and mortality worldwide. Identifying risk factors that affect such infections and their health effects, including environmental exposures to toxicants, such as As, could have a substantial and immediate impact on public health. A recent preliminary study by the applicant demonstrated that exposure of adult mice to As in drinking water compromised their response to a subsequent respiratory influenza infection. The basis for this effect appeared to be related to direct effects of As on the immune response. The overall goal of the proposed research is to determine the underlying mechanism for this effect, focusing in particular on early life exposures. Specifically, we propose to utilize an animal model to investigate the role of in utero As exposure on immune system dysfunction to test the hypothesis that in utero As exposure (via maternal drinking water exposure) followed by a sublethal dose of Influenza A will lead to increased immunopathology in the lung due to a dysfunction CD8+ T cell antiviral response. This hypothesis will be investigated through the following specific aims: 1) Determine the critical time window for inducing immunopathology as a result of in utero and postnatal low dose As exposure (10 ppb) using a mouse adapted strain of H1N1 influenza (PR8) and standardized measures for assessing immunopathology; and 2) Determine the specific role of cytotoxic CD8+ T cells in the increased immunopathology, principally using a transgenic T cell receptor mouse model. There is growing concern about in utero and early childhood exposures to environmental agents and the special nature of these exposures with respect to long term adverse effects on human health. The immune system appears to be specifically vulnerable to early challenges. Understanding the mechanism by which early life exposure to As adversely affects the ability of the immune system to respond effectively to viral and other infections could have a profound impact on our understanding of the overall contribution of such immuno-modulation on a variety of disease risks.

描述（由申请人提供）：慢性砷（AS）暴露被认为是美国和全球环境健康关注的第一种化学物质，并且与多种严重疾病的风险增加有关，包括各种癌症，心血管疾病，糖尿病，糖尿病和其他重要的非癌症疾病风险。暴露的主要途径是摄入饮用水，这种饮用水被无机污染的自然地质来源污染。智利暴露人口的流行病学证据表明，在戒烟后数十年后，在子宫内和幼儿期暴露于支气管扩张死亡风险46倍。这种风险的非凡幅度和意外的残留方面需要进一步调查潜在的机制以及早期生活作为暴露与成人疾病之间的联系。人们认为，复发性呼吸道感染在支气管扩张的发展中起着重要作用。此外，流感等病毒引起的呼吸道感染是全球发病率和死亡率的重要原因。识别影响这种感染及其健康影响的危险因素，包括向毒物（例如毒物）暴露的危险因素，可能对公共卫生产生重大而直接的影响。申请人最近进行的一项初步研究表明，成年小鼠暴露于饮用水中，损害了他们对随后的呼吸道流感感染的反应。这种效果的基础似乎与AS对免疫反应的直接影响有关。拟议的研究的总体目标是确定这种效果的基本机制，尤其是早期生活暴露。具体而言，我们建议利用一种动物模型来研究子宫内的作用，作为免疫系统功能障碍的暴露，以检验以下假设：在子宫内暴露（通过孕妇饮用水暴露），流感损失的剂量会导致由于肺部因肺部病理的增加而导致因肺部病理学的增加而导致因肺部病理学的增加而导致肺部的免疫病理学症状，因为该肺部病理学的增加了。该假设将通过以下特定目的进行研究：1）确定因子宫和产后低剂量作为暴露（10 ppb）的关键时间窗口，使用小鼠适应的H1N1流感菌株（PR8）和评估免疫病理学的标准测量值； 2）确定细胞毒性CD8+ T细胞在增加的免疫病理学中的特定作用，主要是使用转基因T细胞受体小鼠模型。对环境因素的子宫和幼儿期暴露的关注以及这些暴露于长期不良影响对人类健康的特殊性质。免疫系统似乎特别容易受到早期挑战的影响。了解早期生命暴露为不利影响的机制会影响免疫系统对病毒和其他感染有效反应的能力，这可能会对我们对这种免疫调节对各种疾病风险的总体贡献的理解产生深远的影响。