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; 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.

哮喘在美国影响超过1700万人，是发病率的主要原因。最近的角色 非经典HLA I类免疫因子HLA-G。已经提出了哮喘。直接或间接HLA-G 起作用刺激T抑制细胞的存在和功能并下调T辅助器2的活性 （Th2）可能对哮喘发病机理至关重要的细胞。我们实验室的研究表明是HLA-G 哮喘易感性基因，几种关键的单核苷酸多态性（SNP）与哮喘相关 表型，HLA-G的存在在哮喘患者的气道中增加，并且气道上皮细胞 产生HLA-G。我们AADCRC组的最新观察表明，HLA-G在气道中的表达 上皮受到Th2细胞产生的细胞因子的调节，并且在气道中发现了HLA-G的关键受体 平滑肌;激活该受体会刺激平滑肌的增殖和分化。因此，HLA-G 在改变气道内的免疫和结构环境中可能具有关键作用。总体目标 该项目将在轻度和重度的纵向研究中证明存在局部气道HLA-G 哮喘并展示通过气道上皮细胞调节HLA-G局部产生的机制。 我们建议HLA-G在肺部局部表达，在周围可能有助于哮喘表型。 我们进一步建议HLA-G基因型会影响HLA-G的循环和气道丰度 正如我们在项目2中所指出的那样，HLA-G的丰度增加可能导致平滑肌的重要变化 随着时间的流逝，表型恶化了哮喘。为了解决此应用程序中的假设，我们提出了三个 具体目的：1）基于疾病的严重程度和表型检查哮喘中的HLA-G水平。我们假设 哮喘患者的循环和局部气道HLA-G浓度都更高，这些浓度 部分取决于SNP在其3'-非翻译区域（+3142）对HLA-G的调节。 2）确定 Th2细胞因子（例如IL-13）调节HLA-G表达。我们假设IL-13增加 HLA-G在气道上皮的表达和分泌，肺中HLA-G的主要来源， 随着时间的流逝，这为持续的气道炎症提供了积极的反馈。 3）确定调节 miRNA在气道上皮中的HLA-G。我们假设+3142 SNP可变结合的microRNA可以 抑制HLA-G表达，并且这些microRNA是由气道上皮细胞产生的。在一起，这些 研究将清楚地了解HLA-G在哮喘中的作用及其与Th2相关的调节 细胞因子和microRNA，因此为开发新的新疗法奠定了基础。