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.

“健康与疾病的发育起源”（DOHaD）假说认为，生命早期的暴露（营养、环境、炎症）影响后代对多种非传染性疾病的易感性过敏性哮喘是一种影响超过 3 亿人的疾病，其患病率持续增加。与 DoHAD 假说一致，母亲和父亲的暴露会影响疾病的风险和严重程度母亲暴露于环境因素可以通过改变后代哮喘。相比之下，后代 T 细胞和树突状细胞的表观基因组，而特定的父亲暴露（烟草烟雾、特定职业的就业）改变人类后代哮喘风险，影响后代的细胞类型我们的新初步数据表明，怀孕前父亲的 HDM 暴露于过敏原屋尘螨 (HDM) 与哮喘严重程度降低和罗格特募集增加有关在后代中表达 gd T 细胞群，并且后代 gd T 细胞的耗尽会消除保护性父亲接触过敏原的影响已被证明会对后代产生影响。动物模型中代谢功能障碍的行为和/或发展，我们创新的初步数据是首先证明父亲接触过敏原会影响后代的慢性炎症反应。由于 gd T 细胞耗竭逆转了父系过敏原暴露的保护作用，我们捕捉到了父系过敏原暴露的保护作用。 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部中存在的 T 细胞群将在两个独立但相关的实验中进行测试。具体目标 1：确定表达 Rorgt 的 gd T 细胞是否必要且足以减少。 HDM 暴露父亲的后代出现气道高反应性，我们将 1) 在 gd 中有选择地删除 Rorgt 暴露于过敏原的父亲的后代中的 T 细胞，以及 2) 过继转移肺 Roorgt+ gd T 细胞群从对照小鼠或暴露于过敏原的父亲的后代中分离到对照小鼠的肺部。将评估表型以确定肺 gd T 细胞是否是必要和/或足够的介质父系过敏原暴露介导的后代哮喘保护作用目标 2：构建基因调控机制。控制哮喘保护性肺 gd T 细胞的网络 (GRN) 为此，来自后代的肺 gd T 细胞。对照组和暴露于过敏原的父亲将在过敏原致敏之前和之后进行隔离，并使用用于 GRN 构建的 scRNA-seq 和 scATAC-seq GRN 将确定 TF 如何利用增强子和我们将确定与哮喘保护相关的基因表达模式。 gd T 细胞的保护作用是由于子集丰度的变化和/或功能的改变所致。父亲暴露影响免疫细胞功能的细胞和分子机制后代将促进公共卫生并开辟新的研究领域，包括治疗途径哮喘和其他免疫疾病（例如自身免疫性、过敏性）和传染病。