Airway redox biochemistry as a deteriminant of asthma phenotype during adolescen*

描述(由申请人提供)：严重的皮质类固醇不敏感哮喘在大约10%的哮喘人群中被观察到，但占与这种疾病相关的发病率、死亡率和费用的大部分。近10年来，我们团队通过NIH/NHLBI重症哮喘研究计划(SARP)研究了成人和儿童哮喘患者的呼吸道氧化还原障碍。通过创新的代谢组学和氧化还原生物化学方法，这是我们合作努力的优势和独特之处，我们确定了与临床相关的哮喘表型。表型由潜在的生化机制异常的生物标志物定义，包括嗜酸性粒细胞介导的氧化、抗氧化剂和保护性呼吸道S-亚硝硫醇的耗竭和呼吸道酸化。在这里，我们建议研究一种新的成分，它对严重哮喘表型的纵向评估具有信息性：性别效应。严重哮喘对男孩的影响比女孩更大；然而，成人的严重哮喘是一种妇女疾病。年龄相关的性别偏好变化是严重哮喘流行病学的最大信号之一，但仍未得到充分研究。我们认为，确定青春期女性重症哮喘发病的代谢机制(S)，以及男孩重症哮喘的解决，将揭示重症哮喘的基本病理生理机制。重要的是，我们的目标是开发临床测试程序，以准确分配代谢性哮喘表型；并跟踪每个表型的患者，以揭示临床纵向结果。在项目结束时，我们预计我们将有1)开发临床相关的测试来确定严重哮喘的表型；2)确定表型的纵向结果；以及3)确定女性在严重哮喘人群中占多数的机制。 相关性：严重哮喘是一个重大的公共卫生挑战。虽然只有10%到15%的哮喘患者患有严重哮喘，但这些患者在哮喘导致的总医疗费用中占了相对较大的比例。这项应用将专注于开发或临床相关的代谢测试，以确定患有严重哮喘的成人和儿童的亚型，并将导致新的有针对性的创新治疗。

DESCRIPTION (provided by applicant): Severe, corticosteroid-insensitive asthma is observed in ~ 10% of the asthma population but accounts for the majority of the morbidity, mortality and cost associated with the disease. For nearly 10 years our group has studied airway redox disturbances in adults and children with asthma through the NIH/NHLBI Severe Asthma Research Program (SARP). Through innovative metabolomics and redox biochemistry, methodologies that are a strength and unique to our collaborative efforts, we identified clinically relevant phenotypes of asthma. The phenotypes are defined by biomarkers specific to underlying biochemical mechanistic abnormalities, including eosinophil-mediated oxidation, depletion of antioxidants and protective airway S-nitrosothiols, and airway acidification. Here, we propose to study a new component that is informative for longitudinal assessment of severe asthma phenotypes: gender effects. Severe asthma affects boys more than girls; however, severe asthma in adults is a disease of women. The age-dependent change in gender predilection is one of the largest signals in severe asthma epidemiology, but remains understudied. We reason that identification of the metabolic mechanism(s) underlying onset of severe asthma in young women during adolescence, and resolution of severe asthma in boys, will reveal fundamental pathophysiology of severe asthma. Importantly, we aim to develop clinical testing procedures to accurately assign metabolic asthma phenotypes; and to follow patients in each phenotype to uncover clinical longitudinal outcomes. At the conclusion of the project, we anticipate that we will have 1) developed clinically relevant tests to identify severe asthma phenotypes; 2) determined the longitudinal outcome of the phenotypes; and 3) identified the mechanisms underlying the preponderance of women in the severe asthma population. RELEVANCE: Severe asthma is a major public health challenge. Whereas only 10 to 15% of all asthmatics have severe asthma, these patients account for a relatively large fraction of the total health care costs attributed to asthma. This application will focus on the development or clinically relevant metabolic tests to identify subphenotypes of adults and children with severe asthma and will lead to new targeted innovative treatments.