Molecular endotypes and manifestations of chronic rhinosinusitis

慢性鼻-鼻窦炎的分子内型和表现

• 批准号: 10897482
• 负责人: Atsushi Kato
• 金额: $ 55万
• 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/10897482
• 关键词: Molecular; endotypes; manifestations; chronic; rhinosinusitis

PROJECT SUMMARY: The overall goal of the studies in this project is to test the hypothesis that inflammatory endotypes control clinical presentations and comorbid airway diseases in chronic rhinosinusitis (CRS). CRS is one of the most common chronic diseases in adults in the US, affecting approximately 12.5% of Americans, and has a severe impact on patients’ quality of life and healthcare costs. Although CRS is most commonly treated with antibiotics, steroids, and allergy medications, their efficacy is not universal. Due to poor responses to medical therapy, over 400,000 surgical procedures are performed annually in the US. There is therefore an urgent need for a new understanding of the pathogenic mechanisms that drive CRS phenotypes. CRS is clinically classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Both forms are characterized by intense inflammatory cell infiltration which drives symptoms of the disease, but CRSwNP is the more severe form of the two and is characterized by type 2 inflammation including eosinophilia. In contrast to CRSwNP, the mechanism of inflammation in CRSsNP is understudied and poorly understood, despite the fact that over 75% of CRS patients have this phenotype. Although initial studies from Europe suggested that CRSsNP is characterized by type 1 inflammation, we found that only a small subset of patients with CRSsNP did show type 1 inflammation. We therefore hypothesized that inflammation in CRSsNP is more heterogeneous than CRSwNP and this induces variable outcomes of medical treatment. In a preliminary study, we found the overall frequency of CRSsNP with type 1, 2 and 3 inflammation to be 21%, 50% and 27% of patients, respectively. This supports our initial hypothesis and suggests that a pharmaceutical agent targeting a single endotype will not benefit all patients with CRSsNP. A central hypothesis of this project is that inflammatory endotypes control clinical phenotypes of CRS and comorbid airway diseases, and they predict variable outcomes for pharmacological treatments. For example, we have obtained preliminary evidence showing that type 2 inflammation is selectively associated with smell loss and comorbid asthma. In addition, we found that females with CRSwNP have more severe disease than males with CRSwNP. We therefore also hypothesize that sex influences endotype, phenotype and comorbid diseases in CRS. We will collaborate with Project 1 (Immunopathology at Northwestern) and Project 3 (Epidemiology at Geisinger and Johns Hopkins) to test these hypotheses in tertiary care patients at Northwestern and to validate our hypothesis in the general population at Geisinger. Studies in Aim 1 will identify the mechanisms of inflammation for the major endotypes of CRSsNP. Studies in Aim 2 will test the hypothesis that inflammatory endotypes of CRS control clinical presentations and influence comorbidity of lower airway diseases. Studies in Aim 3 will test the hypothesis that sex influences endotype and phenotype of CRS. We believe that the proposed studies will help to identify more precise medicine strategy that effectively prevents disease in CRS patients and avoids unnecessary treatments.

项目摘要：该项目研究的总体目标是检验炎症的假设 内型控制慢性鼻孔炎（CRS）中的临床表现和合并气道疾病。 CRS是 美国成年人中最常见的慢性疾病之一，影响约12.5％的美国人和 虽然CRS是最常见的 使用抗生素，类固醇和过敏药物，它们的效率并非普遍。由于对 医疗疗法，每年在美国进行超过40万手术程序。因此有一个 迫切需要对驱动CRS表型的致病机制进行新的了解。 CRS在临床上 分类为具有鼻息肉（CRSWNP）的CR和无鼻息（CRSSNP）的CR。两种形式都是 以强烈的炎症细胞浸润为特征，导致疾病的症状，但CRSWNP是 两者的更严重形式，其特征是2型炎症，包括嗜酸性粒细胞。与 CRSWNP，CRSSNP中炎症的机制已被理解且理解较低，这是事实 超过75％的CRS患者具有这种表型。尽管欧洲的初步研究表明CRSSNP 以1型炎症为特征，我们发现只有一小部分CRSSNP患者确实显示 1型炎症。因此，我们假设CRSSNP的炎症比 CRSWNP及其影响医疗的可变结果。在一项初步研究中，我们发现了总体 1、2和3炎症的CRSSNP的频率分别为21％，50％和27％的患者。这 支持我们的最初假设，并建议针对单个内型的药物不会 使所有CRSSNP患者受益。该项目的一个核心假设是炎症性内型控制 CRS和合并气道疾病的临床表型，它们预测可变结果 药理治疗。例如，我们获得了初步证据，表明该类型2 炎症有选择地与气味丧失和合并性哮喘有关。此外，我们发现女性 与患有CRSWNP的男性相比，CRSWNP患有更严重的疾病。因此，我们也假设性别 影响CRS中的内型，表型和合并症。我们将与项目1合作 （西北部的免疫病理学）和项目3（盖辛格和约翰·霍普金斯的流行病学）测试这些 西北地区三级护理患者的假设，并验证我们在一般人群中的假设 盖辛格。 AIM 1中的研究将确定CRSSNP主要内型炎症的机制。 AIM 2中的研究将检验以下假设：CRS的炎症性内型控制临床表现和 影响下气道疾病的合并症。 AIM 3中的研究将检验性别影响的假设 CRS的内型和表型。我们认为，拟议的研究将有助于确定更精确的 有效防止CRS患者疾病并避免不必要的治疗的医学策略。