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

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.

项目摘要/摘要