Chronic Rhinosinusitis Integrative Studies Program (CRISP)

描述（由申请人提供）：慢性鼻窦炎（CRS）影响近3000万美国人，每年的直接费用约为60亿美元，每年约有50万例手术。对CRS研究的投资一直不多，我们对CRS的流行病学、遗传学和发病机制的了解也很初步。慢性鼻窦炎综合研究计划（CRISP）项目的主要目标是进行高度合作的研究，以开发有关CRS易感性和严重性的遗传多态性的基础知识;状态，特征，环境风险因素和 CRS的成本;以及严重急性胰腺炎的加重机制和免疫学基础。CRISP有五个主要要素。核心A是由项目PI Robert Schleimer博士领导的行政核心;核心B是由Robert克恩博士领导的临床、实验室和数据管理核心;项目1研究 CRS的流行病学，由Brian Schwartz博士领导;项目2研究CRS的免疫学， 项目3的重点是CRS的遗传学，由Carole Ober博士领导。项目1中的研究定义了Geisinger Health Systems（GHS）大型（> 300，000）初级保健人群中CRS的流行病学。位于芝加哥大学的项目3中的遗传学研究利用来自项目1的2000名患者和对照的样本来识别CRS疾病基因，并将遗传学与疾病状态、严重程度和环境暴露相关联。遗传学研究的候选基因将通过一个基于项目3和项目2之间合作的新系统遗传学发现平台来发现。西北大学的项目1和项目2之间的合作将评估与CRS恶化相关的病原体以及自身免疫在驱动严重疾病中的作用。项目2还将测试B谱系细胞和鼻自身免疫反应在严重鼻分泌性CRS病因学中的重要性。这些合作研究将利用疾病亚表型的改进定义来确定未识别的遗传易感性以及负责CRS发展和严重程度的重要分子和细胞机制。 相关性：慢性鼻窦炎综合研究计划（CRISP）统一和整合了三个世界级的研究小组，以了解慢性鼻窦炎的流行病学，遗传学和病理学。CRISP提出了高度互动的研究，利用西北大学，芝加哥大学和Geisinger卫生系统的人群队列，专业知识和资源，以促进我们对慢性鼻窦炎的理解，并为新的治疗策略指明方向。 项目1：在基于人群的研究中使用新方法验证CRS流行病学 项目负责人（PL）：Schwartz，Brian S. 描述（由申请人提供）：CRS是致残性的，与高直接和间接成本相关，但对流行病学、病因异质性以及个人和社会负担知之甚少。在理解如何制定CRS的研究需求和改善患者结局方面存在巨大差距。该项目将通过利用Geisinger诊所的独特数据和人口资产，包括宾夕法尼亚州30多个县的40万患者的初级保健人口，完成CRS的大规模流行病学研究。我们将联合收割机纵向自我报告和电子健康记录数据与新的临床和研究测量相结合，以解决理解上的差距。虽然对CRS的自然史知之甚少，但很明显：一般人群中的许多患者有鼻和鼻窦症状;其中一些患者被诊断为过敏性鼻炎或ARS发作（症状持续7天至4周，以排除普通感冒患者）;这些患者中的一些进展为CRS，症状存在至少12周;许多CRS患者有急性加重发作，症状明显恶化超过基线;许多患者，特别是在三级中心的患者， 自然史必须包括一些治疗性的，可能是自发的 缓解。研究中每个步骤的发生率、患病率、转换率和风险因素， 框架并不为人所知。由于相对较少的研究存在于人口为基础的样本，很可能大多数研究都集中在治疗失败的患者，即抑郁症组。在拟议的研究中，我们将估计CRS的患病率，发病率和缓解使用临床验证的标准，为一般人群的样本，代表CRS的完整谱;描述CRS恶化和缓解的模式和解释变异的因素;确定CRS与鼻息肉的情况下如何彼此不同;使用现有的地理空间数据对关键环境条件进行评估，评估CRS的各种社区环境风险因素;并估计CRS的直接和间接成本。 相关性：慢性鼻窦炎是一种常见的疾病，可导致患者出现严重症状。它涉及鼻窦炎症，导致面部疼痛/压力，鼻和鼻窦引流，嗅觉丧失和鼻塞。然而，关于有多少人患有这种疾病，谁患有这种疾病，他们为什么会患上这种疾病，以及治疗这种疾病的最佳方法，人们知之甚少。

DESCRIPTION (provided by applicant): Chronic rhinosinusitis (CRS) affects nearly 30 million Americans, has direct costs of approximately $6B annually and is responsible for almost 500,000 surgeries per year. Investment in research on CRS has been modest and our knowledge of the epidemiology, genetics and pathogenesis of CRS is rudimentary. A major goal of the Chronic Rhinosinusitis Integrative Studies Program (CRISP) project is to perform highly collaborative studies to develop fundamental knowledge on the genetic polymorphisms responsible for CRS susceptibility and severity; the states, traits, environmental risk factors and costs of CRS; and the mechanisms of exacerbations and immunological basis of severe recalcitrant disease. CRISP has five main elements. Core A is the administrative Core led by Dr. Robert Schleimer, the PI of the program; Core B is the Clinical, Laboratory and Data Management Core led by Dr. Robert Kern; Project 1 studies the Epidemiology of CRS and is led by Dr. Brian Schwartz; Project 2 studies the Immunology of CRS and mechanisms of exacerbation and is led by Dr. Schleimer; and Project 3 focuses on the Genetics of CRS and is led by Dr. Carole Ober. Studies in Project 1 define the epidemiology of CRS in a large (>300,000) primary care population at Geisinger Health Systems (GHS). The Genetics studies in Project 3, based at the University of Chicago, utilize samples from 2000 patients and controls from Project 1 to identify CRS disease genes and to associate genetics with disease states, severity and environmental exposures. Candidate genes for genetic studies will be discovered via a novel systems genetics discovery platform based on collaboration between Project 3 and Project 2. A collaboration between Project 1 and Project 2, based at Northwestern University, will assess the pathogens associated with exacerbations of CRS and the role of autoimmunity in driving severe disease. Project 2 will also test the importance of B lineage cells and nasal autoimmune responses in the etiology of severe recalcitrant CRS. These collaborative studies will leverage an improved definition of sub-phenotypes of disease to identify unrecognized genetic susceptibilities and important molecular and cellular mechanisms responsible for the development and severity of CRS. RELEVANCE: The Chronic Rhinosinusitis Integrative Studies Program (CRISP) unifies and integrates three world-class research groups to understand the epidemiology, genetics and pathology of chronic rhinosinusitis. CRISP proposes highly interactive studies that leverage the population cohorts, expertise and resources of groups at Northwestern University, the University of Chicago and the Geisinger Health Systems in order to advance our understanding of chronic rhinosinusitis and point the way toward new therapeutic strategies. Project 1: CRS Epidemiology Using New Approaches to Validation in Population-based Studies Project Leader (PL): Schwartz, Brian S. DESCRIPTION (provided by applicant): CRS is disabling and is associated with high direct and indirect costs, yet little is known about the epidemiology, etiologic heterogeneity, and individual and societal burden. There is a substantial gap in understanding how to frame research needs for CRS and improve patient outcomes. This project will complete a large-scale epidemiologic study of CRS by leveraging the unique data and population assets of the Geisinger Clinic, including a primary care population of 400,000 patients in over 30 counties in Pennsylvania. We will combine longitudinal self-reported and electronic health record data with new clinical and research measurements to address gaps in understanding. While relatively little is known about the natural history of CRS, it is clear that: many patients in the general population have nasal and sinus symptoms; some of these patients are diagnosed with allergic rhinitis or episodes of ARS (symptoms for 7d to 4wk, to eliminate patients with the common cold); some of these patients progress to CRS with symptoms present for at least 12 weeks; many patients with CRS have episodes of exacerbations, with a prominent worsening of symptoms over the baseline; many patients, especially those seen in tertiary centers, have recalcitrant CRS; and the natural history must include some therapeutic and probably spontaneous remissions. The incidence, prevalence, transition rates, and risk factors for each of the steps in the framework are not well known. Since relatively little research exists in population-based samples, it is likely that most studies have focused on patients who have failed therapy, the recalcitrant group. In the proposed research, we will estimate CRS prevalence, incidence, and remission using clinically validated criteria for general population samples that represent the ful spectrum of CRS; describe patterns of CRS exacerbation and remission and the factors that explain variability; determine how CRS with and without nasal polyps cases differ from each other; evaluate a variety of community environmental risk factors for CRS using existing geospatial data on key environmental conditions; and estimate the direct and indirect costs of CRS. RELEVANCE: Chronic rhinosinusitis is a common condition that can cause severe symptoms in patients. It involves inflammation of the paranasal sinuses that results in facial pain/pressure, nasal and sinus drainage, smell loss, and nasal obstruction. Little is known however about how many people have the condition, who gets it, why they get it, and the best ways to treat it. The proposed research will address many of these issues.