Airway inflammation and HLA-G in asthma

描述(由申请者提供)：我们的项目旨在阐明导致慢性哮喘的细胞和分子机制，以确定新的、更有效的治疗方法。我们专注于慢性呼吸道炎症的免疫机制，并明确关注一种免疫耐受分子，即I类主要组织相容性复合体蛋白人类白细胞抗原(人类白细胞抗原)-G，我们认为它在调节对慢性哮喘至关重要的气道炎症方面具有重要作用。我们AADCRC建议的关键前提是，了解人类白细胞抗原-G的作用将导致新的和更好的治疗方法，以减轻哮喘造成的痛苦。为此，我们提出了三个高度整合和相关的项目：在项目1中，我们将检测哮喘气道和呼吸道上皮中人类白细胞抗原-G的表达及其调控，并将其与哮喘严重程度和调节microRNA的表达联系起来。我们将研究IL-13等关键Th2细胞因子对HLA-G表达的调节，这些细胞因子对慢性哮喘非常重要，并与慢性哮喘患者的呼吸道细胞因子浓度有关。在项目2中，我们将利用自然发生的人类白细胞抗原-G及其LILRB受体的遗传变异来了解通过人类白细胞抗原-G及其受体的信号如何调节轻/中度哮喘患者的CD4淋巴细胞向Th2表型和重度哮喘患者的Th17表型的转变。该项目还将研究LILRB受体的遗传变异如何调节人类白细胞抗原-G对T细胞表型和SHP1和SHP2信号通路的影响，SHP1和SHP2信号通路调节慢性哮喘患者的气道平滑肌肥大。在项目3中，我们将阐明哮喘母亲的孩子比非哮喘母亲的孩子患哮喘风险更高的机制。我们将以人类白细胞抗原-G作为母子间基因与哮喘状态交互作用的模型，研究慢性哮喘患者呼吸道上皮细胞、CD4T细胞和气道平滑肌中差异表达的基因及其机制。为了完成这些项目，每个项目都将与强大的患者招募和数据分析核心互动，该核心将招募100名仔细分型和基因分型的哮喘受试者和额外的对照受试者，并通过将提供分析和长期存储的肺生物标本核心收集血液和呼吸道生物样本，供每个项目使用。我们相信，我们目前的生产力和协作水平，再加上这项提案中新的、令人兴奋的和前沿的问题，将使我们能够成功地实现我们的总体目标-确定慢性哮喘的新治疗靶点。

DESCRIPTION (provided by applicant): Our program seeks to clarify cellular and molecular mechanisms that lead to chronic asthma in order to identify novel, more effective therapies. We concentrate on immune mechanisms that underlie chronic airway inflammation with a clear focus on one immune tolerance molecule, the class I major histocompatibility complex protein human leukocyte antigen (HLA)-G, that we believe has an important role in modulating airway inflammation that is critical to chronic asthma. The key premise of our AADCRC proposal is that understanding the role of HLA-G will lead to new and better therapies to alleviate the suffering caused by asthma. To this end we propose three highly integrated and related projects: in Project 1, we will examine the presence and regulation of expression of HLA-G in asthmatic airways and in the airway epithelium, and relate presence to asthma severity and to the expression of regulating microRNA. We will examine the regulation of HLA-G expression by key Th2 cytokines such as IL-13 that are important to chronic asthma and relate expression back to airway cytokine concentrations in chronic asthma. In Project 2, we will exploit naturally occurring genetic variations in HLA-G and its LILRB receptors to understand how signaling through HLA-G and its receptors regulate the transition of CD4+ lymphocytes to the Th2 phenotype in mild/moderate asthma and to the Th17 phenotype in severe asthma. This project also will examine how genetic variation in the LILRB receptors modulate the effects of HLA-G on both T cell phenotype and on the SHP1 and SHP2 signaling pathways that modulate airway smooth muscle hypertrophy in chronic asthma. In Project 3, we will elucidate mechanisms that account for the higher risk of asthma among children of asthmatic mothers compared to children of non-asthmatic mothers. Using HLA-G as a model of the interactions of genotype and asthma status in mother and child, we will identify differentially expressed genes and the mechanisms for their differential expression in airway epithelium, CD4+ T cells and airway smooth muscle in subjects with chronic asthma. To complete these projects, each will interact with a robust Patient Recruitment and Data Analysis Core that will recruit 100 carefully phenotyped and genotyped asthmatic subjects and additional control subjects, and collect blood and airway biological specimens to be used in each project through a Lung Biological Specimens Core that will provide analytical and long-term storage. We believe that our current levels of productivity and collaboration combined with new, exciting and cutting-edge questions in this proposal will allow us to be successful in achieving our overall goal - identifying novel therapeutic targets for chronic asthma.