Studies on the Pathogenesis of Chronic Rhinosinusitis

慢性鼻鼻窦炎发病机制的研究

• 批准号: 6909142
• 负责人: JEAN KIM
• 金额: $ 13.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909142
• 关键词: CD40 molecule; CD95 molecule; MHC class II antigen; T lymphocyte; biomarker; clinical research; complementary DNA; flow cytometry; glucocorticoids; human subject; human therapy evaluation; immunocytochemistry; immunomodulators; inflammation; intermolecular interaction; messenger RNA; mucosa; polymerase chain reaction; respiratory disorder chemotherapy; respiratory epithelium; sinusitis; tissue /cell culture

DESCRIPTION (provided by applicant): The pathogenesis of chronic rhinosinusitis (CRS) is characterized by mucosal inflammation with activated epithelial cells and T cells. Exciting new studies from our laboratories show that nasal epithelial cells express B7 homologs, specialized molecules that mediate T cell activation. Our recent in vitro studies show that selected B7 homologs are increased by cytokines and decreased by glucocorticoids. We hypothesize that epithelial cell surface molecules (B7 homologs, HLA-DR, Fas, Fas ligand and CD40) can serve as markers of disease and that exacerbation of sinonasal disease will be associated with increased epithelial costimulators. Based upon our in vitro findings, we hypothesize and that glucocorticoid treatment will inhibit the epithelial response. The primary goal of the studies described in this proposal is to test these hypotheses using a host of specific and reproducible assays to quantitate costimulator expression. Studies in Aim 1 will quantitate expression of costimulatory molecules on sinonasal epithelial cells from control and 4 subgroups of CRS patients with defined disease (CRS alone, CRS with allergic rhinitis, CRS with asthma and CRS with both asthma and aspirin sensitivity (Samter's triad)). Expression of costimulators will be analyzed by Taqman PCR and flow cytometry. These studies will be reinforced by studies employing immunohistochemistry of surgical tissue from the same subjects. Studies in Aim 2 will determine levels of epithelial costimulatory molecule expression in patients before, during and after exacerbations to test the hypothesis that disease exacerbation will be associated with alterations of costimulator expression. We will also examine the in vivo effect of intranasal glucocorticoid treatment on costimulator expression. Studies in Aim 3 will utilize cultured epithelial cells to determine the influence of stimuli likely to participate in CRS (cytokines, toll-like receptor ligands, human rhinovirus and fungal antigens) on costimulator expression and to probe the mechanism of the effect. It is our hope that these studies will give new insight into the factors that modulate epithelial cells in chronic rhinosinusitis.

描述（由申请人提供）：慢性鼻窦炎（CRS）的发病机制以粘膜炎症为特征，上皮细胞和T细胞活化。我们实验室令人兴奋的新研究表明，鼻上皮细胞表达B7同源物，这是一种介导T细胞激活的特殊分子。我们最近的体外研究表明，选定的B7同源物在细胞因子的作用下增加，在糖皮质激素的作用下减少。我们假设上皮细胞表面分子（B7同源物、HLA-DR、Fas、Fas配体和CD40）可以作为疾病的标志物，鼻窦疾病的恶化将与上皮共刺激因子的增加有关。根据我们的体外实验结果，我们假设糖皮质激素治疗会抑制上皮细胞的反应。本提案中描述的研究的主要目标是使用一系列特定和可重复的测定来量化共刺激因子的表达来检验这些假设。Aim 1的研究将量化来自对照和4个特定疾病CRS患者亚组（单独CRS患者、伴有变应性鼻炎的CRS患者、伴有哮喘的CRS患者和同时伴有哮喘和阿司匹林敏感性的CRS患者（Samter’s triad））的鼻上皮细胞共刺激分子的表达。用Taqman PCR和流式细胞术分析共刺激因子的表达。这些研究将通过使用来自同一受试者的手术组织的免疫组织化学研究来加强。Aim 2中的研究将确定患者在病情加重之前、期间和之后的上皮共刺激分子表达水平，以检验疾病加重将与共刺激因子表达改变相关的假设。我们还将研究鼻内糖皮质激素治疗对共刺激因子表达的体内影响。Aim 3的研究将利用培养的上皮细胞来确定可能参与CRS的刺激因子（细胞因子、toll样受体配体、人鼻病毒和真菌抗原）对共刺激因子表达的影响，并探讨其作用机制。我们希望这些研究将为慢性鼻窦炎上皮细胞的调节因素提供新的见解。