Regulation and expression of HLA-G in asthmatic airways

哮喘气道中 HLA-G 的调节和表达

• 批准号: 8196610
• 负责人: STEVEN R WHITE
• 金额: $ 35.28万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196610
• 关键词: 3' Untranslated Regions; Address; Affect; Asthma; Binding; Binding Sites; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cells; Chronic; Complementary DNA; Development; Docking; Environment; Epithelial Cells; Exons; Feedback; Genetic Polymorphism; Genotype; HLA G antigen; Immune; Infection; Inflammatory; Insulin; Interleukin-13; JUN gene; Laboratories; Lead; Lentivirus Vector; Longitudinal Studies; Lung; Mediator of activation protein; MicroRNAs; Morbidity - disease rate; Pathogenesis; Patients; Pattern; Phenotype; Plasma; Predisposition; Production; Proteins; RNA Interference; Refractory; Regulation; Role; Severities; Severity of illness; Signal Pathway; Single Nucleotide Polymorphism; Site; Smooth Muscle; Source; Staging; Suppressor-Effector T-Lymphocytes; Susceptibility Gene; T-Lymphocyte; Time; United States; airway epithelium; airway inflammation; asthmatic airway; base; clinical phenotype; cytokine; disease phenotype; insight; mutant; novel; novel therapeutics; receptor; research study; respiratory smooth muscle; response

Asthma affects over 17 million people in the United States and is a major cause of morbidity. Recently a role for a non-classical HLA class I immune factor, HLA-G. in asthma has been proposed. HLA-G directly or indirectly acts to stimulate the presence and function of T suppressor cells and to down-regulate the activity of T helper 2 (Th2) cells that may be critical to asthma pathogenesis. Studies from our laboratories suggest that is HLA-G an asthma susceptibility gene, that several key single nucleotide polymorphisms (SNPs) correlate with the asthma phenotype, that the presence of HLA-G is increased in the airways of asthmatics, and that airway epithelial cells produce HLA-G. More recent observations from our AADCRC group suggest that HLA-G expression in airway epithelium is regulated by cytokines produced by Th2 cells and that a key receptor for HLA-G is found in airway smooth muscle; activating this receptor stimulates smooth muscle proliferation and differentiation. Thus, HLA-G may have a key role in altering the Immune and structural environment within airways. The overall objectives of this project are to demonstrate the presence of local, airway HLA-G in a longitudinal study of mild and severe asthma and to demonstrate mechanisms that regulate the local production of HLA-G by airway epithelial cells. We propose that HLA-G expressed locally in the lung and in the periphery may contribute to the asthma phenotype. We further propose that HLA-G genotype influences both circulating and airway abundance of HLA-G The increased abundance of HLA-G may lead, as we note in Project 2, to important changes in smooth muscle phenotype that over time worsens asthma. To address our hypotheses in this application, we propose three specific aims: 1) Examine HLA-G levels in asthma based on disease severity and phenotype. We hypothesize that both circulating and local airway HLA-G concentrations are greater in patients with asthma, that these concentrations depend in part on the regulation of HLA-G by a SNP in its 3'-untranslated region (+3142). 2) Determine the regulation of HLA-G expression by Th2 cytokines such as IL-13. We hypothesize that IL-13 increases the expression and secretion of HLA-G in airway epithelium, the principal source of HLA-G in the lung, and that over time this creates a positive feedback for continued airway inflammation. 3) Determine regulation of HLA-G in airway epithelium by miRNA. We hypothesize that the +3142 SNP variably binds microRNA that can suppress HLA-G expression, and that these microRNA are produced by airway epithelial cells. Together, these studies will provide a clear understanding of the role of HLA-G in asthma and its regulation by Th2-associated cytokines and by microRNA, and thus set the stage for the development of novel new therapies.

在美国，哮喘影响超过1700万人，并且是发病的主要原因。最近一个角色， 一种非经典的HLA I类免疫因子，HLA-G。在哮喘中的作用。HLA-G直接或间接 刺激T抑制细胞的存在和功能，下调辅助性T细胞2的活性 (Th2)这些细胞可能对哮喘发病机制至关重要。我们实验室的研究表明，HLA-G是一种 哮喘易感基因是与哮喘相关几个关键的单核苷酸多态性（SNPs HLA-G的存在在哮喘患者的气道中增加， 产生HLA-G。我们的AADCRC组最近的观察表明，气道中HLA-G的表达 上皮细胞受Th 2细胞产生的细胞因子调节，并且在气道中发现HLA-G的关键受体 平滑肌;激活该受体刺激平滑肌增殖和分化。HLA-G 可能在改变气道内的免疫和结构环境中起关键作用。的总体目标 本项目旨在通过对轻度和重度哮喘患者的纵向研究，证明局部气道HLA-G的存在。 哮喘和证明调节气道上皮细胞局部产生HLA-G的机制。 我们认为，HLA-G在肺和外周局部表达可能有助于哮喘表型。 我们进一步提出HLA-G基因型影响循环和气道中HLA-G的丰度 正如我们在项目2中所指出的，HLA-G丰度的增加可能导致平滑肌的重要变化 随着时间的推移，哮喘会恶化的表型。为了解决我们在本申请中的假设，我们提出三个 具体目的：1）基于疾病严重程度和表型检测哮喘中的HLA-G水平。我们假设 哮喘患者的循环和局部气道HLA-G浓度均较高， 部分依赖于HLA-G的3 '-非翻译区（+3142）的SNP对HLA-G的调节。2)确定 Th 2细胞因子如IL-13对HLA-G表达的调节。我们假设IL-13增加 HLA-G在气道上皮中的表达和分泌，气道上皮是肺中HLA-G的主要来源， 随着时间的推移，这会为持续的气道炎症产生积极的反馈。3)确定监管 HLA-G在气道上皮中的表达我们假设+3142 SNP结合了微小RNA， 抑制HLA-G表达，并且这些微小RNA由气道上皮细胞产生。所有这些 研究将提供一个清晰的理解HLA-G在哮喘中的作用及其调节Th 2相关 细胞因子和microRNA，从而为开发新的新疗法奠定了基础。