Transgenerational exposures as modifiers of host defense against infection

跨代暴露作为宿主防御感染的调节剂

• 批准号: 9116844
• 负责人: B Paige Lawrence
• 金额: $ 59.45万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116844
• 关键词: Address; Adult; Adverse effects; Affect; Agonist; Animal Model; Aryl Hydrocarbon Receptor; Binding; Biological Assay; Biological Process; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Child; Clinical; Clonal Expansion; DNA Binding Domain; DNA Methylation; Data; Development; Dioxins; Disease; Disease Outcome; Disease model; Dose; Endocrine system; Environmental Exposure; Environmental Pollution; Epidemiologic Studies; Epigenetic Process; Exhibits; Exposure to; Family; Frequencies; Gene Expression; Generations; Genes; Genetic; Grant; Health; Host Defense; Human; Human Development; Immune response; Immune system; Immunity; Incidence; Individual; Infection; Inflammation; Influenza; Influenza A virus; Inherited; Knock-out; Knowledge; Ligands; Link; Lymphocyte; Lymphocyte Function; Lymphocyte Subset; Maternal Exposure; Measures; Mediating; Modification; Morbidity - disease rate; Mus; Mutant Strains Mice; Nature; Nervous system structure; Outcome; Pathway interactions; Peer Review; Population; Predisposition; Public Health; Reporting; Reproductive system; Research; Research Design; Respiratory Tract Infections; Review Literature; Role; Severities; Sex Characteristics; Signal Transduction; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thinking; Tissues; Toxic effect; Viral; Virus; Virus Diseases; aryl hydrocarbon receptor ligand; base; body system; defined contribution; early life exposure; environmental agent; genome-wide; global health; human disease; immune function; immunoregulation; influenzavirus; mouse model; offspring; parental role; pollutant; prenatal; programs; prototype; response; sex; transgenerational epigenetic inheritance; transmission process; vaccine response

DESCRIPTION (provided by applicant): The objective of this project is to define key parameters involved in transgenerational inheritance of alterations in the function of the mammalian immune system that occur as a result of environmental exposure. The immune system is fundamentally important to public and individual health, and even slight modifications in its function can have a profoundly negative impact on health and disease. For instance, influenza virus infections pose significant global health threats, infecting over 1 billion people annually. Evidence points to prenatal and early life exposure to pollutants as overlooked contributors to poorer clinical outcomes following influenza and other respiratory infections. One family of environmental agents for which there is evidence that developmental exposure affects the function of the immune system in humans and animal models is aryl hydrocarbon receptor (AhR) ligands. For instance, early life exposure to the prototype AhR ligand, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) profoundly disrupts the response of specific lymphocyte subsets to infection in the F1 generation, and exciting pilot data reveal that lymphocyte function is affected in F2 offspring. Other preliminary data support the idea that these changes are due, at least in part, to alterations in DNA methylation. Moreover, TCDD causes transgenerational (F3) effects and altered DNA methylation in other organ systems. Using contemporary, sensitive assays that directly relate to disease outcome, we will further characterize an integrated set of disease-specific T cell responses in the F3 generation, and directly compare these changes to the modified anti-viral immune response observed in F2 and F1 offspring. This comprehensive analysis will include defining the dose-dependent nature of transgenerational effects on T cell functions, and establishing the ligand-specific nature of immune function changes across generations. We will also define the developmental window of susceptibility, basis of sex differences, and role of parental origin in transgenerational inheritance of altered immunity to viral infection. Moreover, we will investigate the mechanism by which AhR ligand exposure transmits aberrant immune function from one generation to the next. We will identify genes and gene networks that are altered in a transgenerational manner using genetic, pathway-specific and genome-wide approaches, and link these changes to alterations in DNA methylation and other epigenetic regulatory mechanisms. The new scientific information generated will have a tremendous impact on public health. Few studies of transgenerational inheritance of the effects of environmental exposures have considered the immune system, or directly evaluated the potential consequences to a disease that affects at least 1 in 7 people each year. Given that TCDD and other AhR ligands cause developmental and transgenerational effects in other tissues, findings from our studies will have a broad impact on efforts to better predict the potential for AhR and its myriad ligands to impinge on many facets of human development and health.

描述（由申请人提供）：该项目的目的是定义与环境暴露有关的哺乳动物免疫系统函数变化的跨代遗传涉及的关键参数。免疫系统对公共和个人健康至关重要，甚至对其功能的稍作修改也可能对健康和疾病产生深远的负面影响。例如，流感病毒感染构成了严重的全球健康威胁，每年感染超过10亿人。证据表明，在流感和其他呼吸道感染后，产前和早期寿命暴露于污染物中，这被忽视了较差的临床结果。有证据表明发育暴露会影响人类和动物模型中免疫系统功能的一种环境药物家族是芳基烃受体（AHR）配体。例如，早期生命暴露于原型AHR配体，2、3、7、8-四氯二苯并-P-二恶英（TCDD）深刻地破坏了F1发电中特定淋巴细胞亚群对感染的反应，而令人兴奋的驾驶员数据表明​​，淋巴细胞功能在F2位式中受到影响。其他初步数据支持以下观点：这些变化至少部分是由于DNA甲基化的改变。此外，TCDD在其他器官系统中引起跨代（F3）效应并改变DNA甲基化。使用与疾病结局直接相关的当代敏感测定，我们将进一步表征F3一代中综合疾病特异性T细胞反应集，并将这些变化与在F2和F1 FOFSPRING中观察到的改良的抗病毒免疫反应直接进行比较。这种全面的分析将包括定义转世对T细胞功能的剂量依赖性，并确定各个一代的免疫功能变化的配体特定性质。我们还将定义易感性的发展窗口，性别差异的基础以及父母来源在转世遗传中的作用，这是对病毒感染免疫的转变遗传。此外，我们将研究AHR配体暴露将异常免疫功能从一代传播到另一代的机制。我们将使用遗传，途径特异性和全基因组方法以跨世代的方式确定基因和基因网络，并将这些变化与DNA甲基化和其他表观遗传调节机制的变化联系起来。产生的新科学信息将对公共卫生产生巨大影响。很少有关于环境暴露影响的跨代遗传的研究已经考虑了免疫系统，或者直接评估了每年至少有7人中至少有1人的疾病的潜在后果。鉴于TCDD和其他AHR配体在其他组织中会引起发育和转世的影响，因此我们的研究结果将对努力产生广泛的影响，以更好地预测AHR及其无数配体的潜力，以影响人类发展和健康的许多方面。