权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10427457
负责人：
Ian Paul Lewkowich
金额：
$ 19.88万
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/10427457
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 Persons Phenotype Pollution Population Predisposition Prevalence Process Public Health Pyroglyphidae Regulation 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 gene regulatory network 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.

"健康和疾病的发育起源"（DOHaD）假设认为，（营养、环境、炎症）影响后代对一些非传染性疾病的易感性疾病过敏性哮喘是一种影响超过3亿人的疾病，其患病率继续增加。与DoHAD假设一致，母亲和父亲的暴露可以影响以下风险和严重程度：后代哮喘母亲暴露于环境因素可以通过改变后代T细胞和树突细胞中的表观基因组。相比之下，虽然特定的父亲暴露（烟草烟雾，在特定职业中的就业）改变人类后代哮喘的风险，影响后代的细胞类型是未知的。我们新的初步数据表明，前概念父亲HDM暴露于过敏原屋尘螨（HDM）与哮喘严重程度降低和罗格特淋巴细胞募集增加有关，在后代中表达gd T细胞群体，并且后代gd T细胞的耗竭消除了保护性免疫应答。父亲过敏原暴露的影响。虽然父亲的暴露已被证明会影响后代行为和/或动物模型中代谢功能障碍的发展，我们的创新性初步数据是首次证明父亲暴露于过敏原会影响后代的慢性炎症反应。由于gd T细胞耗竭逆转了父亲过敏原暴露的保护作用，我们假设父亲过敏原暴露的保护作用可能与gd T细胞耗竭有关。 HDM暴露通过改变表达Rogt的gd的表型和功能降低后代哮喘严重程度 T细胞群存在于肺中。这一创新的假设将在两个独立的，但相关的测试明确的目标。目的1：确定表达Rorgt的gd T细胞是否是减少暴露于HDM的父亲的后代的气道高反应性，我们将1）在gd中选择性删除Lorgt 暴露于变应原的父亲的后代中的T细胞，以及2）过继性转移肺的R 〇 rgt + gd T细胞群从对照组或暴露于变应原的父亲的后代分离的抗原进入对照组小鼠的肺。完全哮喘将评估表型以确定肺gd T细胞是否是肺巨噬细胞增殖所必需的和/或足够的介体。父亲过敏原暴露介导的对后代哮喘的保护。目的2：构建基因调控的调节哮喘保护性肺gd T细胞的GRNs。为此，从小鼠的后代中分离肺gd T细胞，对照组和过敏原暴露的父亲将在过敏原致敏之前和之后被隔离，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，协调与哮喘保护相关的基因表达模式。我们将确定哮喘是否- gdT细胞的保护作用是由于亚群丰度的变化和/或功能的改变。的理解父源暴露影响免疫细胞功能的细胞和分子机制在后代中的应用将促进公共卫生，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）和感染性疾病。