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提出高度合作的研究，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如何 转化为临床表型、自然史和长期结果。该计划重点关注 CRS，无需 鼻息肉（CRSsNP），从目前的角度来看，这是一种非常普遍但模糊的表型 理解。 CRISP2 的另一个重点是批判性评估共病的机制和后果 患者同时患有慢性鼻窦炎和肺部疾病（例如哮喘或支气管扩张）的情况。达到 为了实现这些目标，CRISP2 研究团队的研究人员创新了新的检测方法和方法来切割 发病机制和流行病学的边缘研究，最重要的是，将这两个学科合并起来 将机制与 CRS 的症状、严重程度、病史和结果联系起来。诱导上皮屏障功能障碍 损伤和炎症可导致屏障丧失，从而激活上皮间质转化 (EMT) 在上皮修复过程中。项目 1 研究屏障功能障碍的机制及其在 CRS 严重程度和结果。另一个主题是我们的发现，即组织增生是由沉积物驱动的 交联纤维蛋白。将屏障损失和纤维蛋白沉积联系起来是初步数据，表明 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机制的项目 新定义的慢性鼻窦炎（CRSsNP-HP）表型的变化仅限于鼻窦。屏障功能障碍和 纤维蛋白沉积与免疫内型及其对表型、合并症和疾病的影响有关 评估结果。目标一的研究检验了诱导屏障完整性和功能丧失的假设 由制瘤素 M (OSM)、甲状腺激素和上皮调节蛋白 (EREG) 产生，并与 2 型炎症相关。 将使用一种新型的基于微粒的测定法来监测上皮 EMT，该测定法适用于大量鼻腔 来自 NU（三级护理）和 Geisinger（初级护理）患者队列的灌洗液。单细胞 RNA 测序研究 将评估 CRS 患者样本中的上皮分化和 EMT。第二个目标测试 2 型炎症促进纤维蛋白沉积和增生组织形成的假设，基于 结果表明纤溶途径丧失和纤维形成介质水平增加。我们预测 组织纤维蛋白的生化测量将与内型和增生组织变化相关（息肉> 增生性疾病>>非息肉病）并将监测凝血系统、纤维蛋白溶解和纤维蛋白 在具有明确内型的患者中进行沉积以检验这一假设。第三个目标检验以下假设： 自身免疫性抗磷脂抗体促进 CRS 中的纤维蛋白沉积。我们检测到自身抗体 鼻息肉组织，包括促凝抗磷脂抗体（APA）抗体。我们将评估 APA APA 抗体与 CRSwNP 和 CRSsNP-HP 中纤维蛋白沉积的特异性以及关系。