AsthmaNet: Phenotypic Influences on Asthma Treatments

描述（由申请人提供）：匹兹堡大学AsthmaNet提案包括3个协议，第4个机制协议围绕未满足的哮喘需求和表型构建。这些方案应有助于了解哮喘表型与机制和具体治疗的关系，特别是与健康差异以及种族、社会经济地位（SES）和哮喘严重程度的关系。这些方案建立在我们在哮喘表型和生物学，种族/民族/社会经济问题，环境影响，特别是与服务不足的人群，心理社会压力和严重哮喘相关的固有专业知识基础上。我们的提案包括少数民族健康中心的参与，该中心在少数民族人口的外展方面具有专业知识，凯斯西储彩虹婴儿的合作伙伴和匹兹堡阿勒格尼总医院的卫星。第一项临床试验将比较两种已批准用于治疗成人发作哮喘表型的药物，假设5-脂氧合酶抑制剂比白三烯受体拮抗剂更有效。第二项研究评估了种族与SES对儿童皮质类固醇（CS）反应的关系，认为非裔美国人哮喘表型，无论是否考虑SES，都预示着哮喘儿童对吸入CS的反应较差。补充维生素D将克服不良反应并改善结果。我们将招募非裔美国人和白人儿童，按种族和社会经济地位分层。在初始稳定后仍有症状的儿童将接受高剂量ICS治疗，并确定反应。所有组中未改善的儿童将随机接受维生素D或更高剂量的ICS治疗，以确定维生素D +低剂量ICS是否比高剂量ICS更好地改善急性加重和CS反应性或达到相同程度。机械辅助方案将解决CS无反应性方面是否可以在体外建模，包括种族/SES因素对细胞因子抑制和组蛋白的影响，以及维生素D改善它们的作用。最后，重度哮喘方案将重点关注肥大细胞，特别是前列腺素D2及其与CRTH 2的相互作用。我们相信这些研究解决了哮喘未满足的需求，并将改善其治疗。

DESCRIPTION (provided by applicant): The University of Pittsburgh AsthmaNet proposal includes 3 protocols, with a 4th mechanistic protocol built around unmet asthma needs and phenotyping. These protocols should contribute to understanding asthma phenotypes in relation to mechanisms and specific treatment, particularly in relation to health disparities and contributions from race, socioeconomic status (SES) and asthma severity. These protocols build on our inherent expertise in asthma phenotyping and biology, racial/ethnic/socioeconomic issues, environmental effects, particularly in relation to underserved populations, psychosocial stress, and severe asthma. Our proposal includes participation from the Center for Minority Health with expertise in outreach in minority populations, a partner at Rainbow Babies of Case Western Reserve and a satellite at Allegheny General Hospital in Pittsburgh. The 1st clinical trial will compare two approved drugs for treatment of the adult onset asthma phenotype, which hypothesizes that a 5-lipoxygenase inhibitor will be more effective than a leukotriene receptor antagonist. The 2nd study evaluates the role of race in relation to SES on corticosteroid (CS) responses in children, h3TJ0thesizing that the African-American asthma phenotype, with and without regard to SES, predicts a poor response to inhaled CSs in asthmatic children. Vitamin D supplementation will overcome the poor response and improve outcomes. We will recruit African American and Caucasian children stratified by race and SES. Children who remain symptomatic following initial stabilization will be treated with high dose ICS and response determined. Children of all groups who do not improve will be randomized to treatment with Vitamin D or higher ICS dose to determine whether Vitamin D + lower dose ICS improves exacerbations and CS responsiveness better or to the same degree than the higher dose ICS. The mechanistic ancillary protocol will address whether aspects of CS unresponsiveness can be modeled in vitro, including effects of race/SES factors on cytokine suppression and histones, and the effect of Vitamin D to improve them. Finally, the severe asthma protocol will focus on the mast cell, specifically prostaglandin D2 and its interaction with CRTH2. We believe these studies address unmet needs in asthma and will improve its therapy.