Environmental Influences on Epigenetic Immune Programming

环境对表观遗传免疫编程的影响

基本信息

批准号：
8267796
负责人：
B Paige Lawrence
金额：
$ 2万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2010-12-08 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267796
关键词：
Ablation Address Adoptive Transfer Adult Affect Agonist Antiviral Agents Area Aryl Hydrocarbon Receptor Attention Biological Bone Marrow Bone Marrow Cells CD8B1 gene Cell physiology Cells Chemicals Child Chimera organism Clinical Clonal Expansion DNA Methylation DNA Methyltransferase DNA Modification Methylases Defect Development Dioxins Disease Environmental Exposure Environmental Risk Factor Epidemiology Epigenetic Process Event Exposure to Fetal Tissues Food Chain Gene Expression Gene Targeting Genes Genetic Health Hematopoiesis Hematopoietic Histones Human Immune Immune system Impairment Infection Influenza Influenza A virus Interferon Type II Interferons Knowledge Lead Life Ligands Lymphocyte Maternal Exposure Mediating Methylation Modeling Mus Neonatal Outcome Pathway interactions Peripheral Phenotype Physiological Play Processed Genes Production Proteins Receptor Activation Regulation Regulatory Pathway Reporting Research Resistance to infection Respiratory Tract Infections Role Series Signal Transduction Stem cell transplant T cell response T-Lymphocyte Testing Tetrachlorodibenzodioxin Tissues Virus Virus Diseases aryl hydrocarbon receptor ligand base combat cytokine design early life exposure fetal genome-wide global health histone modification immune function improved influenzavirus innovation neoplastic cell novel offspring pathogen pollutant prenatal programs research study response theories tool tumor vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): We have obtained evidence that developmental exposure to the AhR-specific ligand TCDD (dioxin) affects epigenetically-regulated events leading to long-lasting defects in the offspring's response to influenza A virus infection. Defects include reduced expansion and differentiation of virus-specific CD8+ T cells, impaired production of the antiviral cytokine IFN?. Objectives/Hypothesis: The purpose of this project is to understand how environmental signals delivered via AhR during fetal and neonatal development cause long-lasting impairment of CD8+ T cell responses to infection. Although epigenetic mechanisms are known to regulate gene expression in immune cells, the idea that inappropriate AhR activation during development causes permanent functional changes via an epigenetic mechanism is a novel paradigm. The overall hypothesis for the proposed studies is that inappropriate AhR activation during development interferes with the programming of the immune system via epigenetic mechanisms, resulting in permanent defects in gene expression that lead to long-lasting reductions in CD8+ T cell function. Specific Aims:1) To identify the developmental and lineage-specific targets of AhR that cause long-lasting reductions in the capacity of CD8+ T cells to respond to infection, we will determine the contribution of reprogramming in specific hematopoietic lineages using a combination of progenitor cell transplantation, lineage-specific gene ablation, and adoptive transfer. 2) To identify gene targets whose expression is differentially silenced or activated by developmental exposure to dioxin, we will define AhR-mediated changes in CpG methylation and covalent histone modifications of the ifng locus, and use novel genome-wide approaches to identify additional epigenetically-regulated genes that are affected. 3) To identify epigenetic regulatory pathways modulated by AhR we will use pharmacological and genetic approaches to determine which DNA methyltransferases are affected and whether these changes contribute to impaired CD8? T cell functions, such as impaired IFN? production following infection. Significance: The proposed studies address an area that is relevant to global human health but has received inadequate attention. Influenza and other viral infections continue to pose significant global health threats. Evidence points to prenatal and early life exposure to pollutants as overlooked contributors to poorer clinical outcomes following infection. Moreover, the idea that AhR impacts epigenetic programming is innovative and has broad biological significance, as AhR plays a role in normal hematopoiesis, and developmental exposure to AhR ligands deregulates many aspects of immune function. Moreover, TCDD and other AhR ligands disrupt development of other tissues, thus findings from these studies will help us better understand how AhR ligands impact cells throughout the body, and will provide new information regarding the normal physiological role of AhR.

描述（由申请人提供）：我们获得了证据表明，对AHR特异性配体TCDD（二恶英）的发育暴露会影响表观遗传调节的事件，从而导致后代对流感流感A的反应中的持久缺陷。缺陷包括减少病毒特异性CD8+ T细胞的扩展和分化，抗病毒细胞因子IFN的产生受损。目标/假设：该项目的目的是了解在胎儿和新生儿发育过程中通过AHR传递的环境信号如何导致CD8+ T细胞对感染的持续损害。尽管已知表观遗传机制可以调节免疫细胞中的基因表达，但这种想法是，发育过程中不适当的AHR激活通过表观遗传机制导致永久性的功能变化是一种新的范式。拟议研究的总体假设是，发育过程中不适当的AHR激活通过表观遗传机制干扰免疫系统的编程，导致基因表达的永久缺陷导致CD8+ T细胞功能的长期降低。具体目的：1）为了确定AHR的发育和谱系特异性靶标，这些靶标会导致CD8+ T细胞能力持续降低对感染的反应，我们将确定在特定造血谱系中使用祖细胞细胞移植，谱系特异性基因基因和采用的转移和采用式转移和采用的特定造血谱系中重编程的贡献。 2）为了确定其表达的基因靶标被发育暴露于二恶英而被差异沉默或激活，我们将定义AHR介导的CpG甲基化和IFNG基因座的共价组蛋白修饰的变化，并使用新型基因组方法来识别受影响的其他表观遗传调节基因。 3）为了确定AHR调节的表观遗传调节途径，我们将使用药理学和遗传方法来确定哪些DNA甲基转移酶受到影响，以及这些变化是否有助于CD8受损？ T细胞功能，例如IFN受损？感染后产生。意义：拟议的研究涉及与全球人类健康相关但注意力不足的领域。流感和其他病毒感染继续构成重大的全球健康威胁。证据表明，在感染后，产前和早期寿命暴露于污染物中是较差的临床结果的贡献者。此外，AHR影响表观遗传程序的想法具有创新性，并且具有广泛的生物学意义，因为AHR在正常的造血中发挥了作用，并且对AHR配体的发育暴露会消除免疫功能的许多方面。此外，TCDD和其他AHR配体破坏了其他组织的发展，因此这些研究的发现将有助于我们更好地了解AHR配体如何影响整个身体的细胞，并将提供有关AHR正常生理作用的新信息。