Preconceptual paternal allergen exposure, offspring asthma, and pulmonary gamma/delta T cell function

孕前父亲过敏原暴露、后代哮喘和肺 γ/δ T 细胞功能

基本信息

批准号：
10300217
负责人：
Ian Paul Lewkowich
金额：
$ 23.85万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300217
关键词：
Adoptive Transfer Affect Allergens Allergic Animal Model Anti-Asthmatic Agents Asthma Autoimmune Autoimmune Diseases Automobile Driving Behavior Cell physiology Cells Child Childhood Chronic Communicable Diseases Computational Biology Data Data Set Dendritic Cells Development Diet Disease Employment Enhancers Environmental Risk Factor Exploratory/Developmental Grant Exposure to Extrinsic asthma Fathers Flour Gene Expression Profile Genes Genetic Genetic Predisposition to Disease Genetic Transcription Health Heritability House Dust Mite Allergens Human Immune Immune System Diseases Immune response Immunity Incidence Inflammatory Inflammatory Response Intervention Investigation Life Lung Maternal Exposure Mediating Mediator of activation protein Metabolic dysfunction Molecular Mus Nutritional Occupations Outcome Partner in relationship Paternal Exposure Pathway interactions Phenotype Pollution Population Predisposition Prevalence Process Public Health Pyroglyphidae Regulation Regulator Genes Reporting Research Risk Role Severities Smoking Stimulus Stress T-Cell Depletion T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tobacco smoke Welding airway hyperresponsiveness asthma model base cell type chronic inflammatory disease cigarette smoke early life exposure epidemiology study epigenome genome-wide high reward high risk in vivo inflammatory lung disease innovation insight microbial mouse model network models novel offspring pollutant prenatal exposure protective effect pulmonary function recruit single-cell RNA sequencing therapeutic target transcription factor γδ T cells

项目摘要

The “Developmental Origin of Health and Disease” (DOHaD) hypothesis posits that early life exposures (nutritional, environmental, inflammatory) influence offspring susceptibility to a number of non-communicable diseases. Allergic asthma, a disease affecting >300 million people, continues to increase in prevalence. Consistent with the DoHAD hypothesis, maternal and paternal exposures can influence both risk and severity of offspring asthma. Maternal exposures to environmental factors can influence offspring asthma by modifying the epigenome in offspring T cells and dendritic cells. In contrast, while specific paternal exposures (tobacco smoke, employment in specific occupations) alter offspring asthma risk in humans, the cell types impacted in offspring are unknown. Our novel preliminary data demonstrate that pre-conceptual paternal HDM exposure to the allergen house dust mite (HDM) is associated with a reduced asthma severity and increased recruitment of Rorgt- expressing gd T cell populations in offspring, and that depletion of offspring gd T cells abrogates the protective effect of paternal allergen exposure. While paternal exposures have been demonstrated to influence offspring behavior, and/or development of metabolic dysfunction in animal models, our innovative preliminary data are the first to demonstrate that paternal exposures to allergens influence chronic inflammatory responses in offspring. As gd T cell depletion reversed the protective effects of paternal allergen exposure, we hypothesize that paternal HDM exposure reduces offspring asthma severity by altering the phenotype and function of Rorgt-expressing gd T cell populations present in the lung. This innovative hypothesis will be tested in two independent, yet related specific aims. Aim 1: To determine if Rorgt-expressing gd T cells are necessary and sufficient to reduce airway hyper-responsiveness in offspring of HDM-exposed fathers, we will 1) delete Rorgt selectively in gd T cells in offspring of allergen-exposed fathers, and 2) adoptively transfer lung Rorgt+ gd T cell populations isolated from offspring of control or allergen-exposed fathers into the lungs of control mice. The complete asthma phenotype will be assessed to determine if pulmonary gd T cells are necessary and/or sufficient mediators of paternal allergen-exposure-mediated protection from offspring asthma. Aim 2: Construct the gene regulatory networks (GRNs) governing asthma-protective lung gd T cells. To this end, lung gd T cells from offspring of control and allergen-exposed fathers will be isolated prior to, and after allergen sensitization, and profiled using scRNA-seq and scATAC-seq for GRN construction. The GRN will identify how TFs utilize enhancers and orchestrate gene expression patterns correlated with asthma protection. We will determine whether the asthma- protective role of gd T cells is due to changes in subset abundances and/or altered functionality. An understanding of the cellular and molecular mechanisms through which paternal exposures can influence immune cell function in offspring will advance public health and open up new lines of research, including therapeutic avenues, for asthma and other immune disorders (e.g. autoimmune, allergic) and infectious disease.

“健康与疾病的发展起源”（DOHAD）假设提出早期生活暴露（营养，环境，炎症）影响后代对许多非传染性的敏感性疾病。过敏性哮喘，一种影响3亿人的疾病，患病率不断增加。与DOHAD假设一致，母亲和父亲的暴露会影响风险和严重程度后代哮喘。孕产妇对环境因素的暴露会通过修改来影响后代哮喘后代T细胞和树突状细胞中的表观基因组。相反，虽然特定的父亲暴露（烟草烟雾，但在特定情况下的就业）改变了人类的后代哮喘风险，后代影响的细胞类型是未知的。我们新颖的初步数据表明，概念性父亲的HDM暴露于过敏原房屋尘螨（HDM）与哮喘的严重程度降低并增加Rorgt- 在后代中表达GD T细胞群体，后代GD T细胞的耗竭消除了受保护的父亲过敏原暴露的影响。虽然已经证明父亲暴露会影响后代动物模型中代谢功能障碍的行为和/或开发，我们的创新初步数据是首先证明父亲暴露对过敏原会影响后代的慢性炎症反应。当GD T细胞耗竭逆转父亲过敏原暴露的保护作用时，我们假设父亲 HDM暴露通过改变表达RORGT的GD的表型和功能来降低后代哮喘的严重程度肺中存在的T细胞群体。该创新的假设将在两个独立但相关的两个独立具体目标。目标1：确定表达RORGT的GD T细胞是否需要且足以减少气道在暴露于HDM的父亲的后代中高反应性，我们将在GD中有选择地删除RORGT T细胞在过敏原暴露的父亲的后代和2）自适应转移肺+ GD T细胞种群从对照或过敏原的父亲的后代分离到对照小鼠的肺中。完整的哮喘将评估表型，以确定是否需要肺GD T细胞和/或足够的介体父亲过敏原暴露介导的保护免受后代哮喘的保护。目标2：构建基因调节网络（GRNS）管理哮喘保护性肺GD T细胞。为此，来自后代的肺GD T细胞对照和过敏原暴露的父亲将在过敏原敏感性之前隔离，并使用用于GRN结构的Scrna-Seq和Scatac-Seq。 GRN将确定TFS如何使用增强剂和编排基因表达模式与哮喘保护相关。我们将确定哮喘是否是否 GD T细胞的保护作用是由于子集丰度和/或功能改变的变化所致。一种理解父亲暴露会影响免疫细胞功能的细胞和分子机制在后代将提高公共卫生，并为包括治疗途径在内的新的研究渠道开放哮喘和其他免疫学（例如自身免疫，过敏性）和传染病。