Maternal programming of the stem cell-basophil axis for asthma

哮喘干细胞-嗜碱性粒细胞轴的母体编程

基本信息

批准号：
10441348
负责人：
Magdalena Maria Gorska
金额：
$ 68.96万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441348
关键词：
ATAC-seq Address Allergens Allergic Asthma Basophils Biological Markers Blood specimen Bone Marrow Cell Lineage Cells Child Childhood Asthma Chronic Data Development Diesel Exhaust Embryo Embryo Transfer Enhancers Environment Environmental Exposure Exposure to Female Future Generations Hematopoiesis Hematopoietic Stem Cell subsets Hematopoietic stem cells Histamine Release Human IL3 Gene IL3RA gene IL4 gene IgE Immune response Immune system In Vitro Injections Interleukin-3 Receptor Lead Link Longevity Lymphoid Cell Maternal Exposure Measures Mediating Memory Modeling Molecular Mothers Mus Myeloid Cells Null Lymphocytes PTPRC gene Pathway interactions Phenotype Placenta Population Predisposition Prevention strategy Process Production Radioactivity Radiolabeled Regulator Genes Regulatory Element Reporter Reporting Risk Role Seeds Serum Site Source Stem cell transplant System Testing Tissues Untranslated RNA Up-Regulation asthma model base chromatin remodeling cigarette smoke congenic cytokine diagnostic strategy early embryonic stage epidemiology study experimental study high risk imprint indexing maternal serum meetings mouse model novel diagnostics offspring overexpression particle particle exposure pregnant prevent programs promoter pup self-renewal stem cells synergism transcriptome transcriptome sequencing transmission process treatment strategy

项目摘要

Project Summary/Abstract A growing number of epidemiological studies link childhood asthma with maternal environmental exposures with the strongest evidence provided for diesel exhaust and cigarette smoke. How maternal exposures lead to asthma in offspring is unknown. To address this, we developed a mouse model of asthma susceptibility in pups by exposing their mothers to diesel exhaust particles (DEP). Our data suggests that in this DEP-driven model, asthma-predisposing information is transmitted in part by a subset of offspring long-term hematopoietic stem cells (LT-HSCs), in the form of a stem cell memory. This subset distinguishes itself by expression of the IL3 receptor and is programmed for enhanced generation of basophils by the synergistic action of DEP-induced IL1b and IL3. One key mechanism of the synergism between IL1b and IL3 is the ability of IL1b to increase stem cell sensitivity to IL3 which is in part due to IL1b-mediated upregulation of IL3R b chain. In addition to expanding the basophil lineage, IL3 and IL1b are likely to enhance its capacity to promote asthma. Previous studies show that IL1b potentiates basophil histamine release and IL3 potently stimulates their IL4 production, sowing the seed for type-2 immune response. Consistent with this, in DEP offspring, basophils overexpress IL4. The IL3/IL1b-primed, expanded, IL4-overexpressing basophil population becomes a key driver of the type- 2 immune response and asthma upon allergen challenge. Basophil depletion in DEP pups prevents generation of allergen-specific IgE and development of asthma. This is in contrast with data obtained in plain allergen- based models in which basophils are redundant for production of IgE and asthma. Our overarching hypothesis is that maternal exposure to DEP induces asthma susceptibility in offspring through IL1b and IL3 driven programming of the hematopoietic stem cell-basophil axis. In Aim 1, by performing stem cell transplantation experiments, we will establish links between DEP IL3R+ LT-HSCs, increased basopoiesis and predisposition to asthma. We will define molecular basis of DEP IL3R+ LT-HSC programming by analyzing their transcriptomes (RNA-seq) and chromatin remodeling at gene regulatory sites (ATAC-seq). In Aim 2 we will study importance of IL1b and IL3 in programming of the HSC-basophil axis for asthma induction. In our model, IL1b and IL3 are increased in offspring and maternal tissues, including maternal serum. We propose that maternal IL1b and IL3 are important at early stages of embryonic hematopoiesis, when HSCs undergo their initial divisions and embryonic sources of IL1b and IL3 are scarce. Offspring-derived IL1b and IL3 complete the HSC programming process, sustain basopoiesis at a high level, and contribute to basophil activation after maternal cytokines fade away. To define how maternal IL1b and IL3 are transferred to embryos, study their roles and roles of offspring- encoded IL1b and IL3, we will perform serum transfers, injections with radiolabeled cytokines, and combine IL1b or IL3 KO strategies with embryo transfers. In Aim 3 we will use human blood samples to study IL1b and IL3 guided basophil development in childhood asthma.

项目概要/摘要越来越多的流行病学研究将儿童哮喘与母亲环境暴露联系起来为柴油机尾气和香烟烟雾提供了最有力的证据。母亲接触如何导致后代哮喘尚不清楚。为了解决这个问题，我们开发了幼崽哮喘易感性小鼠模型让她们的母亲接触柴油机尾气颗粒（DEP）。我们的数据表明，在这个 DEP 驱动的模型中，哮喘诱发信息部分由后代长期造血干细胞的子集传递细胞（LT-HSC），以干细胞记忆的形式。该子集通过 IL3 的表达来区分自己受体，并被编程为通过 DEP 诱导的协同作用增强嗜碱性粒细胞的生成 IL1b 和 IL3。 IL1b 和 IL3 之间协同作用的一个关键机制是 IL1b 增加的能力干细胞对 IL3 的敏感性部分归因于 IL1b 介导的 IL3R b 链上调。此外通过扩大嗜碱性粒细胞谱系，IL3 和 IL1b 可能会增强其促进哮喘的能力。以前的研究表明，IL1b 可增强嗜碱性粒细胞组胺的释放，而 IL3 可有效刺激其 IL4 的产生，为 2 型免疫反应播下种子。与此一致的是，在 DEP 后代中，嗜碱性粒细胞过度表达 IL4。 IL3/IL1b引发的、扩增的、IL4过表达的嗜碱性粒细胞群体成为该类型的关键驱动因素。 2 过敏原激发后的免疫反应和哮喘。 DEP 幼崽中的嗜碱性粒细胞耗竭可防止生成过敏原特异性 IgE 和哮喘的发展。这与普通过敏原中获得的数据形成对比基于模型，其中嗜碱性粒细胞对于产生 IgE 和哮喘是多余的。我们的总体假设母亲接触 DEP 会通过 IL1b 和 IL3 驱动，诱发后代哮喘易感性造血干细胞-嗜碱性粒细胞轴的编程。在目标 1 中，通过进行干细胞移植实验中，我们将建立 DEP IL3R+ LT-HSC、增加的碱基生成和易感性之间的联系哮喘。我们将通过分析转录组来定义 DEP IL3R+ LT-HSC 编程的分子基础 (RNA-seq) 和基因调控位点的染色质重塑 (ATAC-seq)。在目标 2 中，我们将研究重要性 IL1b 和 IL3 在 HSC-嗜碱性粒细胞轴编程中的作用以诱导哮喘。在我们的模型中，IL1b 和 IL3 是后代和母体组织（包括母体血清）中增加。我们建议母体 IL1b 和 IL3 在胚胎造血的早期阶段很重要，此时 HSC 经历初始分裂和 IL1b 和 IL3 的胚胎来源很少。子代衍生的 IL1b 和 IL3 完成 HSC 编程过程，维持高水平的嗜碱性粒细胞生成，并在母体细胞因子消失后促进嗜碱性粒细胞活化离开。为了确定母体 IL1b 和 IL3 如何转移到胚胎，研究它们的作用以及后代的作用编码IL1b和IL3，我们将进行血清转移，注射放射性标记的细胞因子，并结合 IL1b 或 IL3 KO 胚胎移植策略。在目标 3 中，我们将使用人类血液样本来研究 IL1b 和 IL3 引导儿童哮喘中嗜碱性粒细胞的发育。