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: 10458540
• 负责人: Robert P Schleimer
• 金额: $ 49.05万
• 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/10458540
• 关键词: Address; Affect; Allergic Disease; Alteplase; Antibodies; Antibody Specificity; Antiphospholipid Antibodies; Asthma; Autoantibodies; Autoimmune; Autoimmunity; B-Lymphocytes; Biochemical; Biological Assay; Biological Markers; Bronchiectasis; Carboxypeptidase U; Cell Differentiation process; Cell Lineage; Coagulation Process; Collaborations; Complement; Data; Deposition; Discipline; Disease; Distal; Epidemiologist; Epidemiology; Epiregulin; Epithelial; Epithelial Cells; Factor XIIIa; Fibrin; Fibrinogen; Fibrinolysis; Functional disorder; Goals; Grant; Hyperplasia; Hyperplastic Polyp; Immunologics; Immunologist; In Vitro; Inflammation; Injury; Interleukin-13; Lead; Link; Lung diseases; Macroglobulins; Measurement; Measures; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Monitor; Nasal Lavage Fluid; Nasal Polyps; Natural History; Nose; Operative Surgical Procedures; Otolaryngologist; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Phospholipids; Plasma Cells; Plasmablast; Polyps; Primary Health Care; Process; Recording of previous events; Research Personnel; Role; Sampling; Severities; Sinus; Symptoms; System; Testing; Thrombin; Thyroid Hormones; Tissues; Translating; base; chronic rhinosinusitis; clinical phenotype; cohort; comorbidity; crosslink; disease heterogeneity; disease phenotype; epithelial repair; epithelial to mesenchymal transition; immunoglobulin B; in vivo; innovation; novel; oncostatin M; overexpression; programs; radiological imaging; response; single-cell RNA sequencing; tertiary care

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.

慢性鼻腔炎综合研究计划2（CRISP2）是一个流行病学家的综合计划， 建议高度协作研究以更好 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，自然历史和长期结果。该计划的重点是没有CRS 鼻息肉（CRSSNP），从电流的角度来看 理解。 Crisp2的另一个重点是批判性地评估合并症的机制和后果 患者患有CRS和肺部疾病（例如哮喘或支气管扩张）的疾病。实现 这些目标，CRISP2研究团队的调查人员已经创新了新的测定法和方法 发病机理和流行病学的边缘研究，最重要的是，这两个学科合并为 将机制与CRS的症状，严重程度，病史和结果相关联。上皮屏障功能障碍，诱导 通过受伤和炎症，可以导致屏障损失，从而激活上皮 - 间质转变（EMT） 在上皮修复过程中。项目1研究了障碍功能障碍的机制及其在 CRS的严重性和结果。另一个主题是我们的发现，即组织增生是由沉积驱动的 交联的纤维蛋白。连接屏障损失和纤维蛋白沉积是初步数据，表明EMT和 纤维蛋白沉积由2型炎症驱动。项目1将是第一个研究增生机制的机制 在新定义的CRS（CRSSNP-HP）的新定义表型中局限于鼻窦的变化。屏障功能障碍和 纤维蛋白沉积将与免疫学内型及其对表型，合并症和 结果评估。 AIM的研究检验了障碍完整性和功能的丧失的假设 由Oncostatin M（OSM），甲状腺激素和环保蛋白（EREG）以及与2型炎症的伴侣。 上皮EMT将通过适用于大量鼻腔的新型基于微粒的测定 NU（三级护理）和Geisinger（初级保健）的患者队列的灌洗液。单细胞RNA-seq研究 将评估CRS患者的样品中的上皮分化和EMT。第二个目标测试 2型炎症促进纤维蛋白的沉积和形成增生组织的假设 结果暗示了纤维蛋白水解途径的丧失和纤维基因介质水平的增加。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>>非型疾病），并将监测凝血系统，纤维蛋白溶解和纤维蛋白 定义内型患者的沉积以检验该假设。第三个目标检验了以下假设 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中APA抗体和纤维蛋白沉积之间的特异性以及APA抗体之间的关系。