ILC2 and epithelial cell heterogeneity and self-sustaining type 2 airway niches in asthma

ILC2 和上皮细胞异质性以及哮喘中自我维持的 2 型气道生态位

基本信息

批准号：
10472534
负责人：
Richard M Locksley
金额：
$ 48.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472534
关键词：
Affect Allergens Allergic Animal Model Animals Area Asthma Attention Biological Response Modifier Therapy Biology Cells Collaborations Complex Development Disease Dissection Eicosanoids Epithelial Epithelial Cells Extrinsic asthma Functional disorder Genetic Genetic Epistasis Goals Goblet Cells Grant Heterogeneity Human Hyperplasia Hypersensitivity Immune Immune System Diseases Immune response Immunity Individual Inflammation Inflammatory Interleukin-13 Interleukin-5 Intestines Lamina Propria Lead Lung Lymphoid Cell Mediating Mediator of activation protein Modeling Mucous Membrane Mucous body substance Mus Nasal Polyps Nasopharynx Neuropeptides Nose Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Polyps Production Publications Publishing Pulmonary Inflammation Recurrence Research Personnel Respiratory System Role Secretory Cell Signal Transduction Site Skin Small Intestines Syndrome System Testing Therapeutic Tissues Trachea Work asthmatic cytokine epidemiology study helminth infection human tissue immune activation immunopathology mouse model novel patient subsets polyposis progenitor programs receptor skills tool tumor-immune system interactions

项目摘要

Project Summary / Abstract This grant seeks to understand the role of Group 2 innate lymphoid cells (ILC2s) in sustaining an altered epithelial interface that is crucial to the establishment of an aberrant remodeled niche that contributes to the persistence of allergic pathology. The proposal is underpinned by publications supported in the prior grant, demonstrating (1) a key role for tissue-elaborated epithelial cytokines in the activation of tissue type 2 immune cells, including ILC2s; and (2) discovery of a feed-forward epithelial-ILC2 circuit in the intestines that drives goblet cell hyperplasia and tissue hyperplasia, providing the impetus for uncovering similar circuitry in the respiratory system. As shown by colleagues in Project 3, severe, drug-recalcitrant, asthma is populated disproportionately with patients with relatively ‘fixed’ airway abnormalities associated with persistent mucus plugs; a significant proportion of individuals also have recurrent nasal polyposis. Together with our discoveries in model animal systems, our over-arching hypothesis is that dysregulated epithelial-ILC2 circuits in the respiratory tract, including nasopharynx (NP), trachea and airways, underlie the presence of persistent niches where allergic pathology is sustained. Using novel genetic tools in mice that permit exquisite dissection of such circuits, we propose 3 Specific Aims that align within the overall goals of the PPG. First, we will define the ILC2 landscape in mouse skin, NP, trachea and lung, where we have uncovered unsuspected diversity that has already been extended to human studies by others in the PPG. Second, we will define the tuft cell landscape in NP and trachea, since the critical role for this enigmatic epithelial cell was uncovered in our intestinal studies. We have demonstrated tuft cell hyperplasia in human allergic polyps. Third, we will use a mouse model of skin inflammation followed by lung allergen challenge to analyze the development of the epithelial-ILC2 circuit from skin to NP to lung, and the role of these respective cells. These findings will be applied to human tissues collected in Core B of this PPG and analyzed in Core C of this PPG to generate discovery in patients with severe asthma. Together, this PPG will uncover dysfunctional cellular networks and niches that sustain allergic immunopathology in the lung.

项目概要/摘要该资助旨在了解第 2 组先天淋巴细胞 (ILC2) 在维持上皮细胞改变中的作用对于建立有助于持久性的异常重塑利基至关重要的界面该提案得到了先前拨款支持的出版物的支持，证明了这一点。 (1) 组织精制上皮细胞因子在组织 2 型免疫细胞激活中的关键作用，包括 ILC2；(2) 发现肠道中驱动杯状细胞的前馈上皮-ILC2 回路增生和组织增生，为揭示呼吸系统中的类似回路提供了动力正如项目 3 的同事所表明的那样，严重的、药物难治性的哮喘患者比例不成比例。患有与持续性粘液栓相关的相对“固定”气道异常的患者；加上我们在模型动物中的发现，有一定比例的个体也患有复发性鼻息肉病。系统中，我们的首要假设是呼吸道上皮-ILC2 回路失调，包括鼻咽 (NP)、气管和气道，是过敏性物质持续存在的环境的基础我们在小鼠中使用新颖的遗传工具来精确解剖此类电路，从而维持病理学。提出与 PPG 总体目标一致的 3 个具体目标首先，我们将定义 ILC2 格局。在小鼠皮肤、NP、气管和肺中，我们发现了意想不到的多样性，这些多样性已经被 PPG 中的其他人将其扩展到人类研究其次，我们将定义 NP 和中的簇细胞景观。气管，因为我们的肠道研究揭示了这种神秘上皮细胞的关键作用。第三，我们将使用小鼠皮肤模型来证明人类过敏性息肉中的簇细胞增生。炎症后进行肺部过敏原激发，以分析上皮-ILC2 回路的发育皮肤、NP、肺，以及这些各自细胞的作用，这些发现将应用于人体组织。在此 PPG 的核心 B 中收集并在该 PPG 的核心 C 中进行分析，以在重症患者中产生发现总之，该 PPG 将揭示维持过敏的功能失调的细胞网络和生态位。肺部的免疫病理学。