ROLE OF EPITHELIUM IN AIRWAY IMMUNITY

上皮在气道免疫中的作用

• 批准号: 8172602
• 负责人: LISA M MILLER
• 金额: $ 15.21万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172602
• 关键词: Allergens; Asthma; Breathing; CCL20 gene; CCR6 gene; Cell Culture Techniques; Cells; Childhood Asthma; Computer Retrieval of Information on Scientific Projects Database; Data; Dendritic Cells; Development; Epithelial Cells; Epithelium; Event; Funding; Grant; Human; Immune response; Immune system; Immunity; Infant; Institution; Interleukin-12; Interleukin-17; Life; Lung; Lymphocyte; Mediating; Monkeys; Pathologic; Phenotype; Play; Population; Prevention; Regulation; Research; Research Personnel; Resources; Role; Source; T-Lymphocyte; Testing; United States National Institutes of Health; age related; airway epithelium; base; candidate identification; chemokine; chemokine receptor; cytokine; drug candidate; infancy; inhibitor/antagonist; nonhuman primate; postnatal; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Little is known about the antecedent events within the human infant lung that predispose the development of pathologic immune responses to inhaled allergens later in life. We do not know if the structural cells of the infant lung can significantly influence the phenotype of an immune response to an inhaled environmental challenge. Of particular significance is the epithelial cell of the conducting airways, which is architecturally and functionally poised to serve as a liaison to the adaptive immune system. The primary objective of this proposal is to determine how the conducting airway epithelium of the infant lung can influence the adaptive immune response to inhaled allergens. Our overall hypothesis is that epithelial cells of the infant lung play a central role in the initiation of the asthma phenotype, via constitutive CCL20 chemokine expression to promote airways recruitment of chemokine receptor CCR6+ T lymphocytes. This hypothesis is based on preliminary data obtained from airway epithelial cell cultures, demonstrating age-dependent expression and inhibitory microRNA regulation of CCL20 via IL-17A. We have also identified a population of IL-17A-producing CCR6+ T lymphocytes in airways of allergen-exposed infant monkeys. Given that human dendritic cells are deficient in IL-12 (a potent inhibitor of IL-17A) during infancy, we further hypothesize that development of the asthma phenotype is initially mediated not by an imbalance of Th2/Th1 cytokines, but rather an imbalance of IL-17A/IL-12. To test these hypotheses, we will 1) investigate the developmental regulation of CCL20 expression in infant airway epithelium, 2) characterize chemokine receptor CCR6+ lymphocyte populations in the infant monkey lung following allergen exposure, and 3) determine the impact of IL-17/IL-12 imbalance on allergen exposed infant monkeys. The experiments proposed within this application will contribute to our overall understanding of how the epithelium of the maturing postnatal lung can direct the development of a pathologic immune response to inhaled allergens. Our findings regarding the contribution of IL-17A in development of asthma in the non-human primate can be directly extrapolated towards identification of candidate drugs for the prevention of childhood asthma. The experiments proposed within this application will contribute to our overall understanding of how the epithelium of the maturing postnatal lung can direct the development of a pathologic immune response to inhaled allergens. Our findings regarding the contribution of IL-17A in the development of the asthma phenotype in non-human primates can be directly extrapolated towards identification of candidate drugs for the prevention of childhood asthma.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 关于人类婴儿肺中的前期事件几乎没有什么了解，这种事件易受病理免疫反应的发展，以后对吸入过敏原的病理反应。我们不知道婴儿肺的结构细胞是否可以显着影响对吸入环境挑战的免疫反应的表型。引导气道的上皮细胞特别重要，该通风道在建筑和功能上准备成为适应性免疫系统的联络。该提案的主要目的是确定婴儿肺的导动气道上皮如何影响对吸入过敏原的适应性免疫反应。我们的总体假设是，婴儿肺的上皮细胞通过组成型CCL20趋化因子表达在哮喘表型的启动中起着核心作用，以促进气道募集趋化因子受体CCR6+ T淋巴细胞的募集。该假设基于从气道上皮细胞培养物获得的初步数据，证明了通过IL-17A对CCL20的年龄依赖性表达和抑制性microRNA调节。我们还确定了暴露于过敏原的婴儿猴子气道中产生IL-17A的CCR6+ T淋巴细胞的种群。鉴于人类树突状细胞在婴儿期缺乏IL-12（IL-17a的有效抑制剂）中，我们进一步假设哮喘表型的发展最初是由TH2/TH1细胞因子的不平衡而不是由IL-17A/IL-12的不平衡的不平衡介导的。为了检验这些假设，我们将1）研究婴儿气道上皮中CCL20表达的发育调控，2）表征趋化因子受体CCR6+淋巴细胞种群在过敏原暴露后，在婴儿猴肺暴露后，以及3）确定IL-17/IL-12 IL-12 IMBALANE对过敏性非生物剂的影响。本应用程序中提出的实验将有助于我们对成熟产后肺上皮的整体理解，如何指导对吸入过敏原的病理免疫反应的发展。我们关于IL-17A在非人类灵长类动物中哮喘发展的贡献的发现可以直接推断出鉴定候选药物以预防儿童哮喘。本应用程序中提出的实验将有助于我们对成熟产后肺上皮的整体理解，如何指导对吸入过敏原的病理免疫反应的发展。我们关于IL-17a在非人类灵长类动物中哮喘表型发展中的贡献的发现，可以直接推断出鉴定候选药物以预防儿童哮喘。