Developmental programming of TCE induced autoimmune disease

TCE诱导的自身免疫性疾病的发育编程

基本信息

批准号：
8927709
负责人：
SARAH J BLOSSOM
金额：
$ 9.97万
依托单位：
ARKANSAS CHILDREN'S HOSPITAL RES INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927709
关键词：
Accounting Adoptive Transfer Adult Adverse effects Age American Autoimmune Diseases Autoimmune Hepatitis Autoimmune Process Autoimmunity Blood CD4 Positive T Lymphocytes Cell physiology Chemical Exposure Chemicals Child Chlorinated Hydrocarbons Country DNA Methylation Development Disease Dose Environmental Pollutants Environmental Pollution Epidemiology Epigenetic Process Etiology Event Exposure to Female Gene Expression Gene Mutation Genes Genome Grant Health Hepatitis Human Immune response Immune system Individual Insulin-Dependent Diabetes Mellitus Knock-out Knowledge Life Lymphocyte Measures Mediating Mus Organic Chemicals Pathology Pregnancy Prevention Preventive Risk Risk Factors Role Scleroderma Solvents Symptoms Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Time Toxic effect Trichloroethylene United States National Institutes of Health Water Pollutants Water Pollution Work Workplace autoreactivity bisulfite drinking water early life exposure experience genome-wide liver inflammation mouse model novel pollutant prevent programs promoter research study superfund site

项目摘要

DESCRIPTION (provided by applicant): Autoimmune diseases are a widespread human health problem. Preventing these incurable disorders is currently impossible due to our limited knowledge of autoimmune disease etiology. There is evidence that idiopathic autoimmune disease can be triggered by exposure to certain environmental pollutants such as the solvent trichloroethylene (TCE). We have shown that adult MRL+/+ mice exposed to low-level TCE developed autoimmune disease along with "heritable" alterations in CD4+ T cell function associated with DNA methylation. Although adult-only exposure to TCE triggered autoimmune disease, there is evidence that the developing immune system is even more sensitive than the adult immune system to chemical toxicity. Thus, developmental exposure to TCE is likely to augment the autoimmune-promoting effects of adult exposure. It is expected that this effect will be mediated by changes in the DNA methylation of specific effector genes in CD4+ T cells. If these predictions are confirmed it would support the concept that developmental exposure to chemicals at levels previously thought safe can promote autoimmune disease development in adults. These predictions and associated mechanism of action will be tested here in 3 Aims. Aim 1. Determine impact of developmental TCE exposure on adult autoimmune disease. We will test whether autoimmune disease pathology and associated CD4+ T cell alterations are more robust if TCE exposure begins at gestation rather than as an adult. Aim 2. Define TCE-induced epigenetic alterations in CD4+ T cells. Novel genome-scale DNA methylation profiles will identify time- and concentration-dependent gene alterations in CD4+ T cells from the TCE-treated mice. Aim 3. Characterize autoreactivity of CD4+ T cells from TCE-treated mice. CD4+ T cells from TCE-treated MRL+/+ mice will be tested for their ability to generate autoimmune disease following adoptive transfer into lymphocyte-deficient (Rag knockout) MRL+/+ mice. This adoptive transfer experiment will compare the autoreactivity of CD4+ T cells generated from two windows of donor TCE exposure (developmental and adult- only).

描述（由申请人提供）：自身免疫性疾病是一个普遍存在的人类健康问题。由于我们对自身免疫性疾病病因学的了解有限，目前不可能预防这些无法治愈的疾病。有证据表明，接触某些环境污染物（例如溶剂三氯乙烯（TCE））可能会引发特发性自身免疫性疾病。我们已经证明，暴露于低水平 TCE 的成年 MRL+/+ 小鼠会出现自身免疫性疾病，并伴有与 DNA 甲基化相关的 CD4+ T 细胞功能的“可遗传”改变。尽管仅成人接触 TCE 会引发自身免疫性疾病，但有证据表明，发育中的免疫系统对化学毒性甚至比成人免疫系统更敏感。因此，发育时期接触三氯乙烯可能会增强成人接触三氯乙烯的自身免疫促进作用。预计这种效应将通过 CD4+ T 细胞中特定效应基因的 DNA 甲基化的变化来介导。如果这些预测得到证实，它将支持这样一个概念：在发育过程中接触以前认为安全的化学物质可以促进成人自身免疫性疾病的发展。这些预测和相关的作用机制将在 3 个目标中进行测试。目标 1. 确定发育期 TCE 暴露对成人自身免疫性疾病的影响。我们将测试如果 TCE 暴露从妊娠期开始而不是在成年时开始，自身免疫性疾病病理学和相关的 CD4+ T 细胞改变是否会更强烈。目标 2. 定义 TCE 诱导的 CD4+ T 细胞表观遗传改变。新型基因组规模的 DNA 甲基化谱将识别 TCE 治疗小鼠的 CD4+ T 细胞中时间和浓度依赖性基因改变。目标 3. 表征 TCE 处理小鼠的 CD4+ T 细胞的自身反应性。将测试来自 TCE 治疗的 MRL+/+ 小鼠的 CD4+ T 细胞在过继转移至淋巴细胞缺陷（Rag 敲除）MRL+/+ 小鼠后产生自身免疫性疾病的能力。该过继转移实验将比较供体 TCE 暴露的两个窗口（发育期和成人期）产生的 CD4+ T 细胞的自身反应性。