Claudin-18 deficiency in the pathogenesis of asthma

Claudin-18 缺乏症与哮喘发病机制的关系

基本信息

批准号：
8522224
负责人：
JAMES A FRANK
金额：
$ 17.64万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522224
关键词：
Accounting Acetylcholine Address Adrenal Cortex Hormones Air Antigens Aspergillus Asthma Breathing Cell Culture Techniques Cells Clinical Data Collaborations Data Defect Development Disease Disease Progression Eosinophilia Epithelial Epithelial Cells Epithelium Exposure to Fibrosis Functional disorder Future Genes Human IgE Immune Immune response Inflammation Integral Membrane Protein Interleukin-13 Interleukin-4 Knockout Mice Label Liquid substance Lung Measures Mediating Messenger RNA Mus Nature Organ Pathogenesis Pathway interactions Permeability Phenotype Predisposition Property Proteins Role Sampling Severities Steroids Structure Testing Tight Junctions Time Tissue Banking Tissue Banks Tissues Wild Type Mouse Work airway epithelium airway hyperresponsiveness airway inflammation asthmatic patient base bronchial epithelium feeding immune activation in vivo knock-down macromolecule mouse model novel response small hairpin RNA translational study

项目摘要

DESCRIPTION (provided by applicant): Dysfunction of the physical barrier of the airway epithelium may contribute to the development of asthma and to disease progression. The nature and mechanisms for epithelial barrier dysfunction in asthma are incompletely understood. This is in part related to the current limited understanding epithelial tight junctions in the airways. Recent discoveries highlight the diversity of tight junction structure and function, and it is clea that tissue-specific differences in tight junction claudin proteins account for differences in epithelial barrier properties in the various tissues of the body. This proposal seeks to define for the first time the role of claudin- 18, the only lung-specific tight junction protein, in airway barier function and asthma. We have found that asthmatics have a deficiency in claudin-18 in the airway epithelium compared with healthy controls. Moreover, untreated asthmatics show an increase in airway epithelial claudin-18 expression with the initiation of steroid treatment. Consistent with this observation, our newly generated claudin-18 knock out mice show a marked susceptibility to antigen sensitization and many features of asthma. Because claudin-18 knock out mice have increased epithelial permeability and claudin-18 knock down results in increased permeability in cultured airway cells, this protein may be a critical component of the airway barrier. Loss of claudin-18 may result in increased antigen exposure and immune activation. Studies in the knock out mouse will allow us to address the hypothesis that an epithelial barrier defect is a primary contributor asthma severity. Importantly, we have also found that IL-13 induces a specific decrease in claudin-18 in primary human airway epithelial cells. Therefore, the specific loss of claudin-18 in response to IL-13 may contribute to epithelial barrie defects in asthma. We will examine the role of claudin-18 maintaining airway epithelial barrier function and determine if the loss of claudin-18 is sufficient to increase airway epithelial permeability to environmental antigen and induce a more severe asthma phenotype in the mouse model of aspergillus sensitization. In cell culture studies using primary human airway epithelial cells grown on an air-liquid interface, we will also investigate the mechanisms for the IL-13-mediated decrease in claudin-18, and the specific contribution of claudin-18 to the airway epithelial permeability barrier. In translational studies using human samples and clinical data collected by the UCSF Airway Tissue Bank, we will investigate the hypothesis that asthmatics with more severe disease have lower levels of claudin-18 and determine if claudin-18 deficiency is associated with asthma Th2 phenotype.

描述（由申请人提供）：气道上皮物理屏障的功能障碍可能有助于哮喘的发展和疾病进展。哮喘中上皮屏障功能障碍的性质和机制尚不完全理解。这部分与当前有限的了解气道上皮紧密连接有关。最近的发现突出了紧密连接结构和功能的多样性，并且紧密连接claudin蛋白的组织特异性差异构成了人体各种组织中上皮屏障特性的差异。该建议旨在定义 Claudin-18的首次是气道巴里尔功能和哮喘中唯一的肺特异性紧密连接蛋白的作用。我们发现，与健康对照相比，哮喘患者在气道上皮中的Claudin-18缺乏。此外，未经治疗的哮喘患者显示，通过类固醇治疗的开始，气道上皮Claudin-18表达增加。与这一观察结果一致，我们新产生的Claudin-18敲除小鼠表明对抗原敏化的敏感性显着，哮喘的许多特征。由于Claudin-18敲除小鼠的上皮渗透性增加，而Claudin-18敲低的敲除导致培养气道细胞的渗透性增加，因此该蛋白可能是气道屏障的关键组成部分。 Claudin-18的丧失可能导致抗原暴露和免疫激活增加。在敲除小鼠中的研究将使我们能够解决上皮屏障缺陷是主要的哮喘严重程度的假设。重要的是，我们也发现 IL-13在原发性人类气道上皮细胞中诱导Claudin-18的特异性降低。因此，响应IL-13的Claudin-18的特定损失可能导致哮喘中上皮肉食缺陷。我们将研究Claudin-18维持气道上皮屏障功能的作用，并确定Claudin-18的丧失是否足以增加气道上皮上皮渗透性对环境抗原的渗透性，并诱导曲植菌敏化小鼠模型中更严重的哮喘表型。在使用在空气界面上生长的原发性人气道上皮细胞的细胞培养研究中，我们还将研究Claudin-18的IL-13介导的降低的机制，以及Claudin-18对Airway上皮通透性屏障的特定贡献。在使用UCSF气道组织库收集的人类样品和临床数据的翻译研究中，我们将研究以下假设：患有更严重疾病的哮喘患者的Claudin-18水平较低，并确定Claudin-18缺乏症是否与哮喘TH2表型有关。