Exploring epigenetic mechanisms of developmental immunology

探索发育免疫学的表观遗传机制

• 批准号: 7226020
• 负责人: B Paige Lawrence
• 金额: $ 14.6万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2008-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226020
• 关键词: Address; Adult; Adult Children; Affect; Agonist; Aromatic Hydrocarbons; Aryl Hydrocarbon Receptor; Attention; Binding; Biochemical; Bioinformatics; Biological Assay; Biological Process; Cell Lineage; Cell physiology; Cells; Chemical Exposure; Chemicals; Collaborations; Congenic Mice; Core Facility; DNA Methylation; Data; Defect; Detection; Development; Dioxins; Dose; Environmental Pollution; Epigenetic Process; Exposure to; Family; Fetus; Flow Cytometry; Gene Expression; Gene Expression Profiling; Genes; Genomics; Goals; Health; Hematopoiesis; Human; Human Milk; Immune System Diseases; Immune response; Immune system; Immunity; Immunology; Immunotoxicology; Inflammation; Interferons; Knowledge; Laboratories; Laboratory Animals; Lactation; Lead; Leukocytes; Life; Ligands; Lung; Lymphocyte; Lymphoid; Lymphoid Tissue; Maternal Exposure; Mediating; Modeling; Molecular; Molecular Biology; Mus; Mutation; Organ; Orphan; Outcome; Patient currently pregnant; Perinatal Exposure; Play; Population; Principal Investigator; Production; Purpose; Receptor Cell; Regulation; Reproductive Biology; Research; Research Personnel; Resources; Role; Schools; Standards of Weights and Measures; Stress; System; T-Lymphocyte; Technical Expertise; Testing; Tetrachlorodibenzodioxin; Tissues; Toxic effect; Toxicology; Transgenic Mice; Transgenic Organisms; Umbilical Cord Blood; Viral; Virus; Virus Diseases; activating transcription factor; base; cell type; cytokine; design; developmental immunology; experience; fetal; fetal programming; immune function; immunotoxicity; imprint; improved; in utero; mature animal; novel; pollutant; programs; receptor; respiratory; response; toxicant

DESCRIPTION (provided by applicant): The overall goal of the proposed project is to obtain a mechanistic understanding of how developmental exposure to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to permanent functional changes in the immune system. TCDD represents a large family of pollutants to which humans are currently exposed. The detection of dioxins and related chemicals in human breast milk and umbilical cord blood has aroused considerable public concern about negative health outcomes from exposure In utero and via lactation. In models using adult animals, TCDD is one of the most immunotoxic compounds known. Dioxin-like compounds are also developmental toxicants; however, very little is known about the mechanisms by which they cause these effects. TCDD and related compounds bind to and activate an orphan receptor, the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor, therefore, alterations in gene expression are believed to underlie the toxicity resulting from fetal exposure to AhR agonists, however this has not been experimentally tested. The overall hypothesis for the proposed studies is that inappropriate activation of the AhR during development interferes with the normal programming of the immune system via epigenetic mechanisms, resulting in permanent defects in gene expression that lead to immune dysfunction later in life. We have preliminary data that support this hypothesis. Specifically, exposure of pregnant mice to TCDD leads to multiple defects in immune function in the adult offspring, including suppressed lymphocyte expansion and differentiation, altered cytokine production, and increased inflammation in the lung. These effects on function occur at developmental doses of TCDD that cause no detectable change in hematopoiesis (i.e., the tissues appear normal, but upon antigenic challenge respond in an abnormal manner). These observations suggest that the effects of TCDD on immune function are long-lasting and may be imprinted by maternal exposure. The proposed studies utilize resources and expertise provided by the Genomics and Bio-Informatics Core Laboratories associated with the Center for Reproductive Biology (CRB). The Principal Investigator has expertise in immunology, toxicology and prior experience with the design and conduct of developmental immunotoxicology research. Collaboration with Dr. Michael Griswold (WSU School of Molecular Biosciences), combined with CRB core facilities brings expertise and technical support in epigenetics, molecular biology, and genomics. Using these resources, the studies described in this application seek to address specific gaps in our knowledge about how chemical exposure at levels below those that are overtly toxic to the fetus result in defects in immune function later in life. Specifically, studies conducted in Aim 1 will determine the role of DNA methylation in defective expression of IFNy. In Aim 2, we will identify the specific cell population(s) responsible for the deregulated T cell function in developmentally exposed mice. Once this critical information is obtained, we will use gene expression profiling to further characterize changes in gene expression within the affected cells, and determine the contribution of epigenetic mechanisms to alterations in the expression of selected genes (Aim 3). Findings from these studies will improve our understanding of the mechanisms that underlie the fetal programming of adult diseases of the immune system.

描述（由申请人提供）：拟议项目的总体目标是获得对污染物2，3，7，8-四氯二苯并-对-二恶英（TCDD）的发育暴露如何导致免疫系统永久功能变化的机理理解。TCDD代表了人类目前接触的一大类污染物。在人类母乳和脐带血中检测到二恶英和相关化学品，引起了公众对子宫内和哺乳期接触二恶英和相关化学品对健康造成的负面影响的极大关注。在使用成年动物的模型中，TCDD是已知最具免疫毒性的化合物之一。二恶英类化合物也是发育毒物;然而，对它们引起这些影响的机制知之甚少。TCDD和相关化合物结合并激活孤儿受体，芳烃受体（AhR）。AhR是一种配体激活的转录因子，因此，基因表达的改变被认为是胎儿暴露于AhR激动剂导致的毒性的基础，但这尚未经过实验测试。 拟议研究的总体假设是，发育过程中AhR的不适当激活通过表观遗传机制干扰免疫系统的正常编程，导致基因表达的永久性缺陷，导致以后生活中的免疫功能障碍。我们有初步数据支持这一假设。具体而言，怀孕小鼠暴露于TCDD会导致成年后代免疫功能的多种缺陷，包括淋巴细胞增殖和分化受到抑制，细胞因子产生改变，以及肺部炎症增加。这些对功能的影响发生在TCDD的发育剂量下，该剂量不会引起造血的可检测变化（即，组织表现正常，但在抗原攻击时以异常方式应答）。这些观察结果表明，TCDD对免疫功能的影响是持久的，可能是由母体暴露的印记。拟议的研究利用与生殖生物学中心（CRB）相关的基因组学和生物信息学核心实验室提供的资源和专业知识。主要研究者具有免疫学、毒理学方面的专业知识，并具有设计和开展发育免疫毒理学研究的既往经验。与Michael格里斯沃尔德博士（WSU分子生物科学学院）的合作，结合CRB核心设施，带来了表观遗传学，分子生物学和基因组学方面的专业知识和技术支持。使用这些资源，本申请中描述的研究试图解决我们关于低于对胎儿明显有毒的水平的化学品暴露如何导致生命后期免疫功能缺陷的知识中的具体差距。具体地，在目标1中进行的研究将确定DNA甲基化在IFN γ的缺陷性表达中的作用。在目标2中，我们将鉴定发育暴露小鼠中导致T细胞功能失调的特定细胞群。一旦获得这些关键信息，我们将使用基因表达谱来进一步表征受影响细胞内基因表达的变化，并确定表观遗传机制对选定基因表达改变的贡献（目的3）。这些研究的结果将提高我们对免疫系统成人疾病胎儿编程机制的理解。