Environmental Influences on Epigenetic Immune Programming

环境对表观遗传免疫编程的影响

• 批准号: 8204752
• 负责人: B Paige Lawrence
• 金额: $ 35.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/8204752
• 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; public health relevance; research study; response; theories; tool; tumor; vaccine efficacy

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. PUBLIC HEALTH RELEVANCE: Recent studies reveal that prenatal and early life exposure to pollutants is an overlooked but important contributor to poorer outcomes following viral infection; however, how developmental exposures cause long- lasting defects in immune function is not clear. Using a model developmental immunotoxicant and influenza A virus as a prototypical human pathogen, the proposed research will determine how developmental exposure reprograms the offspring's immune system. This research addresses growing concern about how environmental factors contribute disease, and will improve our understanding of epigenetic regulation within the context of the developing immune system.

描述（由申请人提供）：我们已获得证据表明，发育过程中暴露于 AhR 特异性配体 TCDD（二恶英）会影响表观遗传调控事件，从而导致后代对甲型流感病毒感染的反应出现长期缺陷。缺陷包括病毒特异性 CD8+ T 细胞的扩增和分化减少，抗病毒细胞因子 IFNα 的产生受损。目标/假设：本项目的目的是了解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 细胞对感染反应的长期损害。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功能变化的想法是一个新颖的范例。拟议研究的总体假设是，发育过程中不适当的 AhR 激活会通过表观遗传机制干扰免疫系统的编程，导致基因表达永久性缺陷，从而导致 CD8+ T 细胞功能长期下降。具体目标：1) 为了确定 AhR 的发育和谱系特异性靶点，这些靶点会导致 CD8+ T 细胞对感染的反应能力长期降低，我们将结合祖细胞移植、谱系特异性基因消融和过继转移来确定重编程在特定造血谱系中的贡献。 2) 为了鉴定其表达因发育暴露于二恶英而差异沉默或激活的基因靶标，我们将定义 AhR 介导的 CpG 甲基化变化和 ifng 位点的共价组蛋白修饰，并使用新的全基因组方法来鉴定受影响的其他表观遗传调节基因。 3) 为了确定 AhR 调节的表观遗传调控途径，我们将使用药理学和遗传学方法来确定哪些 DNA 甲基转移酶受到影响以及这些变化是否会导致 CD8 受损？ T 细胞功能，例如干扰素受损？感染后的生产。意义：拟议的研究涉及与全球人类健康相关但尚未引起足够重视的领域。流感和其他病毒感染继续对全球健康构成重大威胁。有证据表明，产前和生命早期接触污染物是导致感染后临床结果较差的被忽视的因素。此外，AhR 影响表观遗传编程的想法是创新的，具有广泛的生物学意义，因为 AhR 在正常造血中发挥作用，而发育过程中暴露于 AhR 配体会放松免疫功能的许多方面的调节。此外，TCDD和其他AhR配体会破坏其他组织的发育，因此这些研究结果将帮助我们更好地了解AhR配体如何影响全身细胞，并将提供有关AhR正常生理作用的新信息。 公共卫生相关性：最近的研究表明，产前和生命早期接触污染物是导致病毒感染后预后较差的一个被忽视但重要的因素；然而，发育暴露如何导致免疫功能的长期缺陷尚不清楚。使用模型发育免疫毒剂和甲型流感病毒作为典型的人类病原体，拟议的研究将确定发育暴露如何重新编程后代的免疫系统。这项研究解决了人们日益关注的环境因素如何导致疾病的问题，并将提高我们对免疫系统发育过程中表观遗传调控的理解。