Clinical and Molecular Phenotypes of Severe Asthma

严重哮喘的临床和分子表型

• 批准号: 8849948
• 负责人: John V Fahy
• 金额: $ 68.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849948
• 关键词: Accounting; Adult; Affect; Allergic Bronchopulmonary Aspergillosis; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Aspergillus fumigatus; Asthma; Base Sequence; Binding; Biochemical; Bioinformatics; Biologic Characteristic; Biological; Biological Assay; Biological Markers; Biological Process; Biology; Biopsy; Blood; Blood specimen; Blood typing procedure; Candidate Disease Gene; Cells; Characteristics; Chest; Child; Chronic; Clinical; Collaborations; DNA; Data; Development; Disease; Doctor of Philosophy; Elasticity; Epigenetic Process; Frequencies; Fucose; Functional disorder; Galactose; Galactose Binding Lectin; Galectin 3; Genetic; Genomics; Guidelines; Heterogeneity; Infection; Inflammation; Inflammatory; Knowledge; Laboratories; Lectin; Longitudinal Studies; Measures; Mediating; Messenger RNA; MicroRNAs; Molecular; Molecular Profiling; Morbidity - disease rate; Mucins; Mucolytics; Mucous body substance; Oligosaccharides; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Polymers; Polysaccharides; Predisposition; Property; Protocols documentation; Public Health; Radiology Specialty; Reaction Time; Reading; Research Design; Research Personnel; Respiratory physiology; Rheology; Role; Saliva; Sampling; Sputum; Subgroup; Techniques; Testing; Therapeutic; Time; Transcript; airway inflammation; airway remodeling; asthmatic; base; burden of illness; clinical phenotype; crosslink; design; epigenome; follow-up; fucose-binding protein; genome wide association study; improved; inhibitor/antagonist; microbial colonization; microbiome; molecular phenotype; mortality; mucus hypersecretion; novel; outcome forecast; programs; response; targeted treatment; treatment response; viscoelasticity

DESCRIPTION (provided by applicant): Severe asthma is a heterogeneous disease with distinct clinical phenotypes characterized by differences in susceptibility to exacerbation, loss of lung function, chronic mucus hypersecretion, and refractoriness to anti- inflammatory therapy. Our objectives are to define severe asthma phenotypes at the molecular and cellular level longitudinally in order to predict prognosis, identify novel treatment targets, and guide targeted therapy. Our overarching hypothesis is that differences in clinical presentation, outcomes, and response to therapy in severe asthma are driven by: 1) distinct types of airway inflammation and remodeling developed and maintained by specific molecular pathways; 2) microbial colonization or infection; 3) genetic/epigenetic factors. Aim 1 proposes a shared longitudinal protocol to identify and validate phenotypic characteristics of severe asthma based on underlying pathobiology and pathophysiology. Our protocol incorporates a two- phase design with an initial six-month phase of supervised guideline-based therapy to document baseline clinical and molecular phenotypes, the stability of these phenotypes over time, and response to standardized therapy. This initial phase will be followed by a 2.5 year follow-up phase to document exacerbation frequency and rate of loss of lung function. Aim 2 will explore mechanisms of pathologic mucus in severe asthma in two sub-aims that will both use rheology to quantify the viscoelastic properties of induced sputum from patients with chronic severe asthma. We will identify subgroups of severe asthmatics with chronic mucus hypersecretion and abnormal mucus rheology, determine the clinical and biological characteristics of these subgroups, and explore in ex vivo studies the role of multimeric lectins as cross-linkers of mucin polymers and potential targets of glycomimetic therapy. Included in the lectins we will study will be Aspergillus fumigatus lectin, a fucose binding lectin that we hypothesize to have a pathogenic role in the mechanism of mucus plug formation in Allergic Bronchopulmonary Aspergillosis, an important subtype of severe asthma. RELEVANCE: Severe asthma occurs in 5-10% of asthmatics and accounts for much of the public health burden of the disease. Patients with severe asthma have unmet therapeutic needs because many respond sub-optimally to currently available treatments. To improve treatment for severe asthma it will be necessary to have a better understanding of the mechanisms of disease to guide targeted therapy.

描述（由申请人提供）：重度哮喘是一种异质性疾病，具有不同的临床表型，其特点是易加重、肺功能丧失、慢性粘液分泌过多和抗炎治疗难治。我们的目标是在分子和细胞水平纵向定义严重哮喘表型，以预测预后，确定新的治疗靶点，并指导靶向治疗。我们的总体假设是，严重哮喘的临床表现、结果和治疗反应的差异是由以下因素驱动的：1)不同类型的气道炎症和重构由特定的分子途径发展和维持；2)微生物定植或感染；3)遗传/表观遗传因素。目的1提出了一种基于潜在病理生物学和病理生理学的共享纵向协议，以识别和验证严重哮喘的表型特征。我们的方案包括两个阶段的设计，最初的六个月阶段是有监督的基于指南的治疗，以记录基线临床和分子表型，这些表型随时间的稳定性，以及对标准化治疗的反应。初始阶段之后将进行为期2.5年的随访，以记录急性加重频率和肺功能丧失率。目的2将在两个子目标中探讨病理性粘液在严重哮喘中的机制，这两个子目标都将使用流变学来量化慢性严重哮喘患者诱导痰的粘弹性特性。我们将确定慢性黏液高分泌和黏液流变异常的严重哮喘亚群，确定这些亚群的临床和生物学特征，并在体外研究中探索多聚凝集素作为黏液聚合物交联剂的作用和拟糖治疗的潜在靶点。我们将研究的凝集素包括烟曲霉凝集素，这是一种病灶结合凝集素，我们假设它在过敏性支气管肺曲霉病（一种严重哮喘的重要亚型）的粘液堵塞形成机制中起致病作用。