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的人类健康问题。由于我们对自身免疫性疾病病因的了解有限，目前不可能防止这些无法治愈的疾病。有证据表明，特发性自身免疫性疾病可以通过暴露于某些环境污染物（例如溶剂三氯乙烯（TCE））来触发。我们已经表明，暴露于低级TCE的成年MRL+/+小鼠出现了自身免疫性疾病，以及与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引发了自身免疫性疾病，但有证据表明，发育中的免疫系统比成人免疫系统对化学毒性更敏感。因此，发育暴露于TCE可能会增加成人暴露的自身免疫性作用。预计这种作用将通过CD4+ T细胞中特定效应基因的DNA甲基化的变化介导。如果确认这些预测将支持以前认为安全水平上的化学物质的发育暴露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暴露在妊娠时而不是成年，则自身免疫性疾病病理和相关的CD4+ T细胞改变是否更健壮。 AIM 2。定义TCE诱导的CD4+ T细胞中的表观遗传学改变。新型的基因组尺度DNA甲基化谱将发现来自TCE处理的小鼠的CD4+ T细胞中的时间和浓度依赖性基因改变。 AIM 3。表征来自TCE处理的小鼠CD4+ T细胞的自动反应性。来自TCE处理的MRL+/+小鼠的CD4+ T细胞将通过继承转移到淋巴细胞缺陷型（RAG敲除）MRL+/+小鼠后产生自身免疫性疾病的能力。该收养转移实验将比较从两个供体TCE暴露窗口（仅发育和成人）中产生的CD4+ T细胞的自动反应性。