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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：
10217812
负责人：
Lora Bankova
金额：
$ 22.52万
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/10217812
关键词：
Afferent Neurons Airway Disease Allergens Allergic Disease Alternaria Apnea Asthma Biological Assay Bronchoconstriction Brush Cell Cell Culture Techniques 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 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.

项目总结：孤立性化学感觉细胞是一种罕见的特殊上皮细胞，散布在呼吸道(称为刷状细胞)中细胞)和肠粘膜(称为簇状细胞)，最近被发现是2型免疫反应的发起者至少部分是通过产生促炎细胞因子IL-25。在呼吸道中，刷子的激活细菌代谢物的苦味也会触发感觉神经元，从而产生保护性的呼吸道反射。化学感觉细胞和激活味觉受体以外的受体的全部效应潜力尚未被已定义。我们已经发现，上皮细胞与来自气管的化学感觉细胞具有相同的转录特征和肠道丰富在鼻黏膜中。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，并开发了一种体外系统来测试配体受体对这会激活呼吸道刷状细胞。我们发现，刷状细胞会产生大量的亲- 炎性脂质介质，其中半胱氨酰白三烯(CysLts)。然后我们产生了一只新的小鼠刷状细胞中CysLT末端产生酶基因缺失的菌株刷细胞来源的CysLTs对呼吸道的促炎和保护反应。在目标1中，我们将定义来自呼吸道和嗅觉粘膜的鼻刷细胞亚群细胞RNA测序。在目标2中，我们将定义触发刷状细胞激活的信号通路空气变应原感知，自分泌环路增强这种反应和刷状细胞的全部效应潜力。在目标3中，我们将确定刷状细胞来源的CysLts在呼吸道上皮细胞激活中的作用小鼠具有刷状细胞、CysLTs和刷状细胞特异性缺失的CysLTs。这里的发现将阐明刷状细胞来源的CysLTs在呼吸道保护和炎症反应中的作用为进一步明确其在人呼吸道粘膜中的功能奠定了基础。拟议中的实验结果将为保护性呼吸道反应提供关键的见解旨在驱逐环境侮辱的东西可以被转移到启动和传播炎症反应导致过敏性呼吸道疾病。