Mechanisms of barrier dysfunction and tissue hyperplasia in CRS

CRS中屏障功能障碍和组织增生的机制

• 批准号: 10897481
• 负责人: Robert P Schleimer
• 金额: $ 44万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10897481
• 关键词: Mechanisms; barrier; dysfunction; tissue; hyperplasia

The Chronic Rhinosinusitis Integrative Studies Program 2 (CRISP2) is an integrated program of epidemiologists, otolaryngologists, allergists and immunologists in which highly collaborative studies are proposed to better understand the molecular and cellular mechanisms of disease heterogeneity and how these mechanisms translate into clinical phenotypes, natural history and long term outcomes. The program focuses on CRS without nasal polyps (CRSsNP), a highly prevalent and yet obscure phenotype from the standpoint of current understanding. Another focus of CRISP2 is to critically evaluate the mechanisms and consequences of comorbid conditions in which patients have both CRS and lung disease such as asthma or bronchiectasis. To achieve these goals, the investigators on the CRISP2 study team have innovated new assays and approaches to cutting edge studies of pathogenesis and epidemiology and, most importantly, have merged these two disciplines to relate mechanisms to symptoms, severity, history and outcomes of CRS. Epithelial barrier dysfunction, induced by injury and inflammation, can lead to barrier loss, which activates epithelial-mesenchymal transition (EMT) during the epithelial repair process. Project 1 investigates the mechanisms of barrier dysfunction and its role in CRS severity and outcomes. Another topic follows our findings that tissue hyperplasia is driven by deposition of cross-linked fibrin. Linking barrier loss and fibrin deposition are preliminary data suggesting that both EMT and fibrin deposition are driven by type 2 inflammation. Project 1 will be the first to study mechanisms of hyperplastic changes confined to the sinuses in a newly defined phenotype of CRS (CRSsNP-HP). Barrier dysfunction and fibrin deposition will be related to immunological endotype and their influence on phenotype, comorbidity and outcomes assessed. Studies in aim one test the hypothesis that loss of barrier integrity and function is induced by oncostatin M (OSM), thyroid hormone and epiregulin (EREG), and associates with type 2 inflammation. Epithelial EMT will be monitored with a novel microparticle-based assay applicable to large numbers of nasal lavage fluids from patient cohorts at NU (tertiary care) and Geisinger (primary care). Single cell RNA-Seq studies will evaluate epithelial differentiation and EMT in samples from patients with CRS. The second aim tests the hypothesis that type 2 inflammation promotes fibrin deposition and formation of hyperplastic tissue, based on results implicating loss of fibrinolytic pathways and increased levels of fibrogenic mediators. We predict that biochemical measurement of tissue fibrin will correlate with endotype and hyperplastic tissue changes (polyps > hyperplastic disease >> non-polypoid disease) and will monitor the coagulation system, fibrinolysis and fibrin deposition in patients with defined endotypes to test this hypothesis. The third aim tests the hypothesis that autoimmune antiphospholipid antibodies promote fibrin deposition in CRS. We have detected autoantibodies in nasal polyp tissues, including procoagulant anti-phospholipid antibodies (APA) antibodies. We will evaluate APA specificity and the relationship between APA antibodies and fibrin deposition in CRSwNP and CRSsNP-HP.

慢性鼻窦炎综合研究计划2(CRISP2)是流行病学家的综合计划， 耳鼻喉科医生、过敏症专家和免疫学家，他们建议进行高度合作的研究，以更好地 了解疾病异质性的分子和细胞机制以及这些机制是如何 转化为临床表型、自然病史和长期结果。该计划专注于CRS，没有 鼻息肉(CRSsNP)，一种高度流行但又鲜为人知的表型 理解。CRISP2的另一个重点是批判性地评估共病的机制和后果 患者既有CRS又有肺部疾病的情况，如哮喘或支气管扩张。要实现 为了实现这些目标，CRISP2研究团队的研究人员创新了切割的新分析和方法 病因学和流行病学的前沿研究，最重要的是，将这两个学科合并为 CRS的发病机制与症状、严重程度、病史和转归有关。上皮屏障功能障碍，诱导性 通过损伤和炎症，可导致屏障丧失，从而激活上皮-间充质转化(EMT)。 在上皮修复过程中。项目1调查屏障功能障碍的机制及其在 CRS的严重程度和预后。另一个主题跟随我们的发现，组织增生是由沉积的 交联型纤维蛋白。初步数据表明，屏障丧失和纤维蛋白沉积均提示EMT和 纤维蛋白沉积是由2型炎症驱动的。项目1将是第一个研究增生性疾病机制的项目 一种新定义的CRS表型(CRSsNP-HP)中仅限于鼻窦的变化。屏障功能障碍和 纤维蛋白沉积将与免疫内型有关，及其对表型、合并症和 评估结果。目标一的研究验证了屏障完整性和功能丧失是由 通过抑癌素M(OSM)、甲状腺激素和表观调节素(Ereg)，并与2型炎症有关。 上皮性EMT将用一种新的基于微粒的分析方法进行监测，该方法适用于大量鼻腔 从NU(三级护理)和Geisinger(一级护理)的患者队列中灌洗液体。单细胞RNA-SEQ研究 将评估CRS患者样本中的上皮分化和EMT。第二个目标是测试 假设2型炎症促进纤维蛋白沉积和增生性组织的形成，基于 结果提示纤溶途径缺失，致纤维化介质水平升高。我们预测 组织纤维蛋白的生化测定将与内型和增生性组织变化相关(息肉和GT； 增生性疾病和非息肉性疾病)，并将监测凝血系统、纤溶和纤维蛋白 有明确内型的患者的沉积来验证这一假说。第三个目标是检验假设 自身免疫抗磷脂抗体促进CRS中纤维蛋白沉积。我们检测到自体抗体在 鼻息肉组织，包括促凝剂抗磷脂抗体(APA)抗体。我们将评估APA CRSwNP和CRSsNP-HP的特异性及APA抗体与纤维蛋白沉积的关系