Airway inflammation and HLA-G in asthma

描述（由申请人提供）：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。我们专注于慢性气道炎症背后的免疫机制，明确关注一种免疫耐受分子，I类主要组织相容性复合物蛋白人白细胞抗原(HLA)-G，我们认为它在调节气道炎症中起重要作用，这对慢性哮喘至关重要。我们AADCRC提案的关键前提是了解HLA-G的作用将导致新的和更好的治疗方法来减轻哮喘引起的痛苦。为此，我们提出了三个高度整合和相关的项目：在项目1中，我们将研究哮喘气道和气道上皮中HLA-G的存在和表达调控，并将其与哮喘严重程度和调节microRNA的表达联系起来。我们将研究关键Th2细胞因子如IL-13对慢性哮喘的调节，并将其表达与慢性哮喘气道细胞因子浓度联系起来。在项目2中，我们将利用自然发生的HLA-G及其LILRB受体的遗传变异，了解通过HLA-G及其受体的信号传导如何调节CD4+淋巴细胞在轻度/中度哮喘中向Th2表型转变，在重度哮喘中向Th17表型转变。该项目还将研究LILRB受体的遗传变异如何调节HLA-G对T细胞表型和调节慢性哮喘气道平滑肌肥大的SHP1和SHP2信号通路的影响。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。利用HLA-G作为基因型与母亲和儿童哮喘状态相互作用的模型，我们将确定慢性哮喘受试者气道上皮、CD4+ T细胞和气道平滑肌中差异表达的基因及其差异表达的机制。为了完成这些项目，每个项目都将与一个强大的患者招募和数据分析中心进行互动，该中心将招募100名仔细表型和基因分型的哮喘受试者和额外的对照受试者，并通过肺生物标本中心收集血液和气道生物标本，用于每个项目，该中心将提供分析和长期存储。我们相信，我们目前的生产力和合作水平，结合本提案中新的，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.