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

气道氧化还原生物化学作为青春期哮喘表型的决定因素*

• 批准号: 8572752
• 负责人: Serpil C. Erzurum
• 金额: $ 51.8万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8572752
• 关键词: Abbreviations; Accounting; Address; Adolescence; Adrenal Cortex Hormones; Adult; Affect; Antioxidants; Asthma; Behavioral; Biochemical; Biochemistry; Biological Markers; Blood Vessels; Cell Count; Child; Classification; Clinic; Clinical; Collection; Development; Disease; Eotaxin; Epidemiology; Estradiol; Evolution; Exhalation; Female; Formates; Functional disorder; Gender; Health Care Costs; Injury; Lead; Longitudinal Studies; Lung; Male Adolescents; Mediating; Menstrual cycle; Metabolic; Methodology; Molecular; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Patients; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Population; Prevalence; Principal Investigator; Procedures; Puberty; Public Health; Recording of previous events; Research; Resolution; Respiratory physiology; S-Nitrosothiols; Serum; Severities; Signal Transduction; Spirometry; Staging; Stem cells; Superoxide Dismutase; Testing; Testosterone; Tyrosine; United States National Institutes of Health; Urine; Visit; Whole Blood; Woman; age related; boys; clinically relevant; cost; eosinophil; ethyl nitrite; girls; improved; innovation; male; metabolomics; mortality; nitrosative stress; novel; oxidation; programs; repository; reproductive function; research clinical testing; response; urinary; young woman

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.

描述（由申请人提供）：严重的皮质类固醇不敏感哮喘约占哮喘人群的10%，但占与该疾病相关的发病率、死亡率和成本的大部分。近10年来，我们小组通过NIH/NHLBI严重哮喘研究计划（SARP）研究了成人和儿童哮喘患者的气道氧化还原障碍。通过创新的代谢组学和氧化还原生物化学，这些方法是我们合作努力的优势和独特之处，我们确定了哮喘的临床相关表型。表型由特定于潜在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，抗氧化剂和保护性气道s -亚硝基硫醇的消耗，以及气道酸化。在这里，我们建议研究一个新的组成部分，为严重哮喘表型的纵向评估提供信息：性别影响。严重哮喘对男孩的影响大于女孩；然而，成人严重哮喘是一种女性疾病。性别偏好的年龄依赖性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，确定青春期年轻女性严重哮喘发病的代谢机制，以及男孩严重哮喘的消退，将揭示严重哮喘的基本病理生理学。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；并跟踪每一种表现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)开发临床相关测试来识别严重哮喘表型；2)确定表型的纵向结果；3)确定了女性在严重哮喘人群中占主导地位的机制。