Exploring the biology of persistent type 2 airway niches in asthma

探索哮喘持续性 2 型气道生态位的生物学

基本信息

批准号：
10681265
负责人：
John V Fahy
金额：
$ 243.9万
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/10681265
关键词：
ATAC-seq Address Allergic inflammation Anions Asthma Basophils Behavior Bioinformatics Biology Bronchoscopy CRISPR/Cas technology Cell Differentiation process Cell Fate Control Cell Reprogramming Cells Cellular biology Chest Clinical Collaborations Communication Cytometry Data Development Disease Effector Cell Epidemiologist Epigenetic Process Epithelial Cells Epithelium Faculty Gel Gene Expression Genes Genetic Goblet Cells Health Human Immune Immune response Immunity Immunologist Inflammation Inflammatory Response Inhalation Injury Interleukin-13 Interleukin-5 Intervention Investigation Ligands Lung Lung CAT Scan Lymphocyte Mediating Messenger RNA Methods Methylation MicroRNAs Mucins Mucous body substance Mus Myelogenous Nasal Polyps Nature Otolaryngologist Oxidants Pathogenesis Pathologic Pathology Patient imaging Patients Production Program Research Project Grants Publications RNA analysis Research Research Personnel Role Sampling Scientist Secretory Cell Seminal Signal Transduction Source System T-Lymphocyte Technology Testing Th2 Cells Tissues Training United States National Academy of Sciences Work X-Ray Computed Tomography airborne allergen airway epithelium airway inflammation asthmatic patient biobank crosslinking and immunoprecipitation sequencing curative treatments cytokine eosinophil eosinophil peroxidase epithelial injury high dimensionality human subject image guided immune checkpoint innovation lung imaging mast cell member multidisciplinary novel novel therapeutics programs radiologist receptor receptor function recruit repaired response sensor success transcription factor transcriptome sequencing transcriptomics

项目摘要

Summary / Abstract This is a renewal application for a PPG that focuses on mechanisms of persistence of type 2 inflammation in asthma. The central theme of our PPG is that the focal nature of type 2 inflammation that occurs in asthma reflects the development of persistent “type 2 airway niches” that are characterized by epithelial cell and immune cell reprogramming and mucus plug formation. Normal homeostatic responses to aeroallergens and other inhaled insults include communications between epithelial cells and innate cells to recruit adaptive cells that limit type 2 immune responses and restore airway function. When these repair mechanisms fail the normal airway immune program is replaced by adaptive responses that favor persistence of airway type 2 inflammation and formation of mucus plugs. This persistent and “ultra high” type 2 inflammation occurs in focal regions of the asthma lung, as evidenced by our recent finding of focal and persistent eosinophilic mucus plugs in lung images from patients with asthma. Our PPG will explore the biology of these focal type 2 airway niches in three overarching aims. AIM 1 will determine how innate and adaptive immune cells in the persistent airway type 2 niche are reprogrammed to sustain inflammation. AIM 2 will determine how airway epithelial cells are reprogrammed in type 2 niches to sustain inflammation. AIM 3 will determine how epithelial cells and eosinophils sustain mucus gel pathology in type 2 airway niches. Our PPG comprises three projects led by multidisciplinary teams of clinical scientists, immunologists and cell biologists. The projects are supported by three cores - administration, human subjects, and biospecimens and bioinformatics. Our PPG proposes innovative concepts for the pathogenesis of type 2-high asthma and it will deploy powerful and cutting edge technologies in the experimental approaches that address our program aims. We are united in our ambition to aim for discoveries that have the potential to lead to curative treatments for type 2-high asthma.

摘要/摘要这是 PPG 的更新应用，重点研究 2 型炎症持续存在的机制。我们 PPG 的中心主题是哮喘中发生的 2 型炎症的焦点性质。反映了持续的“2型气道生态位”的发展，其特征是上皮细胞和免疫细胞重编程和粘液栓形成对空气过敏原和其他物质的正常稳态反应。吸入性损伤包括上皮细胞和先天细胞之间的通讯，以招募适应性细胞，从而限制当这些修复机制无法正常气道时，会产生 2 型免疫反应并恢复气道功能。免疫程序被有利于气道 2 型炎症持续存在的适应性反应所取代这种持续且“超高”的 2 型炎症发生在粘液栓的局部区域。肺部哮喘，我们最近在肺部图像中发现局灶性和持续性嗜酸性粘液栓就证明了这一点我们的 PPG 将在三个方面探索这些局灶性 2 型气道生态位的生物学。 AIM 1 将确定 2 型持续气道中的先天性和适应性免疫细胞的总体目标。生态位被重新编程以维持炎症，AIM 2将决定气道上皮细胞的状态。在 2 型微环境中重新编程以维持炎症的 AIM 3 将如何决定上皮细胞和嗜酸性粒细胞。我们的 PPG 包括由多学科领导的三个项目。该项目由临床科学家、免疫学家和细胞生物学家组成的团队由三个核心支持—— 我们的 PPG 提出了创新概念。针对 2 型高哮喘的发病机制，它将在我们团结一致，致力于实现我们的计划目标。这有可能导致 2 型高哮喘的治愈性治疗。

项目成果

期刊论文数量（69）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolic consequences of obesity as an "outside in" mechanism of disease severity in asthma.

肥胖的代谢后果作为哮喘疾病严重程度的“由外向内”机制。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Peters, Michael C;Fahy, John V
通讯作者：
Fahy, John V

A Novel Air Trapping Segment Score Identifies Opposing Effects of Obesity and Eosinophilia on Air Trapping in Asthma.

一种新颖的空气滞留段评分确定了肥胖和嗜酸性粒细胞增多对哮喘空气滞留的相反影响。

DOI：
发表时间：
2023-12-19
期刊：
影响因子：
24.7
作者：
Leung, Clarus;Tang, Monica;Huang, Brendan K;Fain, Sean B;Hoffman, Eric A;Choi, Jiwoong;Dunican, Eleanor M;Mauger, David T;Denlinger, Loren C;Jarjour, Nizar N;Israel, Elliot;Levy, Bruce D;Wenzel, Sally E;Sumino, Kaharu;Hastie, Annette T;Schi
通讯作者：
Schi

MicroRNA-mediated regulation of T helper cell differentiation and plasticity.

MicroRNA 介导的 T 辅助细胞分化和可塑性调节。

DOI：
发表时间：
2013-09
期刊：
影响因子：
0
作者：
Baumjohann, Dirk;Ansel, K Mark
通讯作者：
Ansel, K Mark

Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology.

哮喘鼻气道转录组关联研究揭示了基因驱动的粘液病理学。

DOI：
发表时间：
2022-03-28
期刊：
影响因子：
16.6
作者：
Sajuthi, Satria P;Everman, Jamie L;Jackson, Nathan D;Saef, Benjamin;Rios, Cydney L;Moore, Camille M;Mak, Angel C Y;Eng, Celeste;Fairbanks;Salazar, Sandra;Elhawary, Jennifer;Huntsman, Scott;Medina, Vivian;Nickerson, Deborah A;Germ
通讯作者：
Germ

Airway mucus function and dysfunction.

气道粘液功能和功能障碍。