Brush cell sensing of aeroallergen-elicited stress signals promotes epithelial cell activation

刷细胞感知空气过敏原引起的应激信号促进上皮细胞活化

基本信息

批准号：
10361506
负责人：
Lora Bankova
金额：
$ 21.15万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2021-03-02 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361506
关键词：
Afferent Neurons Allergens Allergic Disease Alternaria Apnea Asthma Biological Assay Bronchoconstriction Brush Cell Cell Degranulation Cells Chronic Data Data Set Eicosanoid Production Eicosanoids Enzymes Epithelial Epithelial Cells Event Foundations Functional disorder Gene Expression Profile Generations Genetic Goals Goblet Cells Heterogeneity Human Immune Immune response Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intestinal Mucosa Intestines Lead Ligands Link Mediating Mediator of activation protein Methods Mouse Strains Mucins Mucous Membrane Mus Names Nasal Epithelium Nerve Nose Olfactory Mucosa Pathway interactions Population Receptor Signaling Reflex action Reporting Respiratory Mucosa Role Signal Pathway Signal Transduction Site Sneezing Source Specialized Epithelial Cell Stress Structure of mucous membrane of nose System Taste Buds Taste Perception Techniques Testing Tissues Trachea Vasodilation Virus Work afferent nerve airborne allergen allergic airway disease antimicrobial autocrine base cellular targeting chronic respiratory disease chronic rhinosinusitis cysteinyl leukotriene receptor 2 cysteinyl-leukotriene cytokine defined contribution design experimental study in vivo insight leukotriene-C4 synthase lipid mediator mast cell neuroinflammation novel programs receptor respiratory respiratory reflex response sensory system single-cell RNA sequencing transcriptome sequencing

项目摘要

PROJECT SUMMARY: Solitary chemosensory cells are rare specialized epithelial cells scattered in the airway (referred to as brush cells) and intestinal mucosa (named tuft cells), recently found to be initiators of type 2 immune responses at least partially through the generation of the proinflammatory cytokine IL-25. In the airways, activation of brush cells by bitter tasting bacterial metabolites also triggers sensory neurons leading to protective airway reflexes. The full effector potential of chemosensory cells and activating receptors beyond taste receptors have not been defined. We have found that epithelial cells sharing the transcriptional profile of chemosensory cells from the trachea and intestine are enriched in the nasal mucosa. We generated a nasal brush cell RNA-seq data set to determine their possible activating receptors and developed an ex vivo system to test the ligand receptor pairs that lead to activation of airway brush cells. We found that brush cells generate large quantities of pro- inflammatory lipid mediators among them cysteinyl leukotrienes (CysLTs). We then generated a new mouse strain with genetic deletion of the terminal CysLT generating enzyme in brush cells to define the contribution of brush cell-derived CysLTs to the pro-inflammatory and protective responses in the airways. In Aim 1, we will define the subsets of nasal brush cells from the respiratory and olfactory mucosa using single cell RNA sequencing. In Aim 2, we will define the brush cell activating pathways triggered in response to aeroallergen sensing, the autocrine loops enhancing this response and the full effector potential of brush cells. In Aim 3, we will define the role of brush cell-derived CysLTs in epithelial cell activation in the airways using mice with genetic deletion of brush cells, CysLTs and brush cell-specific deletion of CysLTs. Findings here will clarify the contribution of brush cell-derived CysLTs to protective and inflammatory responses in the airways and lay the foundation to define their function in human airway mucosa. Results from the proposed experiments will provide critical insights into how protective airway responses designed to expel environmental insults can be diverted to initiate and propagate inflammatory responses leading to allergic airway diseases.

项目摘要：孤立的化学感应细胞是散布在气道中的罕见的专业上皮细胞（称为刷子细胞）和肠粘膜（称为簇簇细胞），最近被发现是2型免疫反应的发起者通过产生促炎性细胞因子IL-25的生成最少。在气道中，激活刷子细胞通过苦味细菌代谢产物还会触发感觉神经元，从而导致防护性气道反射。化学感应细胞和激活受体超出味觉受体的全部效应器潜力尚未是定义。我们发现上皮细胞共享气管化学感应细胞的转录曲线肠和肠富含鼻粘膜。我们生成了一个鼻刷细胞RNA-seq数据集确定其可能的激活受体，并开发出一个离体系统来测试配体受体对这导致气道刷电池的激活。我们发现刷子细胞会产生大量的促值炎症性脂质介质中有白细胞三烯（CYSLTS）。然后我们生成了一只新鼠标用终端Cyslt产生刷细胞中的酶的遗传缺失，以定义将源自孔道促炎和保护性反应的刷子衍生的Cyslt刷出。在AIM 1中，我们将使用单个呼吸道和嗅觉粘膜定义鼻刷细胞的子集细胞RNA测序。在AIM 2中，我们将定义响应于 Aeroallergen感应，自分泌环增强了这种反应和刷子细胞的全部效应潜力。在AIM 3中，我们将使用刷子细胞衍生的CYSLT在使用刷子细胞衍生的CYSLT中的作用具有刷牙细胞，Cyslts和Cyslt的刷细胞特异性缺失的遗传缺失的小鼠。这里的发现会阐明刷子细胞衍生的Cyslt对气道保护和炎症反应的贡献并奠定基础来定义其在人类气道粘膜中的功能。拟议的实验的结果将提供有关保护气道响应的关键见解旨在驱逐环境侮辱的目的可以转移以发起和传播炎症反应导致过敏性气道疾病。