Chronic Rhinosinusitis Integrative Studies Program 2 (CRISP2)

慢性鼻窦炎综合研究计划 2 (CRISP2)

基本信息

批准号：
10458536
负责人：
Robert P Schleimer
金额：
$ 183.38万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10458536
关键词：
Address Airway Disease Asthma Attention Basic Science Biological Assay Biological Markers Bronchiectasis CD8-Positive T-Lymphocytes Case-Control Studies Cells Chronic Clinical Coagulation Process Congestive Data Collection Deposition Development Diagnostic Procedure Disease Disease Outcome Early identification Electronic Health Record Epidemiologist Epidemiology Epithelial Evaluation Fibrin Fresh Tissue Functional disorder Goals Grant Headache Hyperplasia Immunologics Immunologist Inflammation Inflammatory Integrins Knowledge Laboratories Link Longitudinal Studies Lung diseases Lymphoid Cell Macroglobulins Mediating Medical Research Mesenchymal Modeling Molecular Nasal Lavage Fluid Nasal Polyps Natural History Natural Killer Cells Nose Operative Surgical Procedures Otolaryngologist Outcome Outpatients Pain Pathogenesis Pathogenicity Patients Pharmacologic Substance Phenotype Physicians Play Population Prevalence Prevention Primary Health Care Principal Investigator Process Quality of life Research Retrospective Studies Retrospective cohort Retrospective cohort study Risk Risk Factors Role Sampling Severities Sex Differences Sinus Smell Perception Smooth Muscle Actin Staining Method Study Subject Symptoms System Taste Perception Testing Th1 Cells Th2 Cells Time Tissues Translating Visit Vulnerable Populations Woman base chronic rhinosinusitis clinical care clinical phenotype cohort comorbidity cost cytokine data management disease heterogeneity eosinophil epidemiology study experience insight macrophage mast cell men neutrophil novel population based programs protective factors repaired response sample collection single-cell RNA sequencing tertiary care transcriptome sequencing

项目摘要

The Chronic Rhinosinusitis Integrative Studies Program 2 (CRISP2) is an integrated program of epidemiologists, otolaryngologists, allergists and immunologists with highly collaborative studies 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. There is a compelling need for more research in chronic rhinosinusitis (CRS). Patients with CRS experience a dramatic decrement in quality of life, CRS has a prevalence approaching 12%, nearly half a million patients per year undergo surgery and the estimated total costs of CRS in the US are $22-32 billion per year. Hypotheses and themes of CRISP2 are: 1.) Heterogeneous underlying pathogenic mechanisms yield variable clinical phenotypic manifestations; 2.) Comorbidity of sinus disease and lung disease tracks with selected molecular endotypes; 3.) There are profound differences between mechanisms and manifestations of CRS in men and women; 4.) Pathogenic mechanisms of CRSsNP, the more prevalent form of disease, have not been well studied; 5.) There is a significant need to study CRS in primary care populations; 6.) New assays are needed to evaluate molecular endotypes in an outpatient setting. This grant addresses all of these hypotheses and themes. Relating molecular endotypes to clinical manifestations, natural history, comorbidity and outcomes of disease is an overarching goal of this program. Three projects and two cores (Administrative Core A and Clinical, Laboratory and Data Management Core B) comprise the CRISP2 program. The three main project main aims are: Project 1-To study the mechanisms of epithelial barrier dysfunction and tissue hyperplasia in CRS. Project 1 will use a novel microparticle (MP) based assay of epithelial differentiation and will assay components of the coagulation and fibrinolytic systems to test the hypothesis that fibrin deposition, barrier dysfunction and epithelial mesenchymal transition (EMT) play important pathogenic roles in CRS. These responses will be related to immunological endotypes, clinical phenotypes, comorbidity and clinical outcomes. Project 2-To dissect molecular endotypes and relate them to manifestations of CRS. Project 2 will test the hypothesis that inflammation in CRS is heterogeneous and that inflammatory endotypes control clinical phenotypes of CRS. Preliminary results implicate select endotypes as inducers of certain symptom constellations and have led to hypotheses about the cells and molecules that drive the main immunological endotypes, type 1, 2 and 3. Both Project 1 and Project 2 will utilize large sample sets from patients at both Geisinger (Project 3) and NU (Core B). Project 3-To use population-based CRS epidemiology to evaluate sex differences, natural history, and long-term outcomes based on clinically-defined phenotypes and biologically- based endotypes. Large retrospective cohort and longitudinal epidemiological studies proposed include an ongoing study of nearly 8000 study subjects; an EHR-based retrospective study of 10,000 patients and 20,000 controls; a longitudinal study of 450 subjects; and case-control studies of risk factors for bronchiectasis.

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如何转化为临床表型、自然史和长期结果。迫切需要对慢性病进行更多研究鼻窦炎（CRS）。 CRS 患者的生活质量急剧下降，CRS 患病率很高接近 12%，每年近 50 万患者接受手术，CRS 的估计总费用在美国每年为 22-320 亿美元。 CRISP2 的假设和主题是： 1.) 异构底层致病机制产生不同的临床表型表现； 2.) 鼻窦疾病的合并症和肺部疾病与选定的分子内型相关； 3.) 机制之间存在深刻差异男性和女性 CRS 的表现； 4.) CRSsNP的致病机制，更为普遍疾病的形式，尚未得到充分研究； 5.) 非常需要研究初级保健中的 CRS 人口； 6.) 需要新的测定方法来评估门诊环境中的分子内型。这笔补助金解决所有这些假设和主题。将分子内型与临床表现、自然现象联系起来疾病的病史、合并症和结果是该计划的首要目标。三个项目和两个核心（管理核心 A 和临床、实验室和数据管理核心 B）包含 CRISP2 程序。三个主要项目的主要目标是：项目 1-研究上皮屏障的机制 CRS 中的功能障碍和组织增生。项目 1 将使用一种新型的基于微粒 (MP) 的上皮细胞检测方法分化，并将分析凝血和纤溶系统的成分，以检验以下假设：纤维蛋白沉积、屏障功能障碍和上皮间质转化（EMT）起着重要的致病作用 CRS 中的角色。这些反应将与免疫内型、临床表型、合并症和临床结果。项目 2 - 剖析分子内型并将其与 CRS 的表现联系起来。项目 2 将检验以下假设：CRS 中的炎症是异质的并且炎症内型控制 CRS 的临床表型。初步结果表明选择的内型是某些症状的诱导剂星座并导致了关于驱动主要免疫学的细胞和分子的假设内型，类型 1、2 和 3。项目 1 和项目 2 都将利用来自两个患者的大量样本集 Geisinger（项目 3）和 NU（核心 B）。项目3-利用基于人群的CRS流行病学评估性别基于临床定义的表型和生物学的差异、自然史和长期结果基于内型。拟议的大型回顾性队列和纵向流行病学研究包括近 8000 个研究对象的持续研究；一项基于 EHR 的回顾性研究，涉及 10,000 名患者和 20,000 名患者控制；对 450 名受试者的纵向研究；以及支气管扩张危险因素的病例对照研究。