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个方案，第4个机制方案围绕未满足的哮喘需求和表型建立。这些方案应该有助于理解哮喘表型与机制和特定治疗的关系，特别是与种族、社会经济地位（SES）和哮喘严重程度的健康差异和贡献有关。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，特别是与服务不足人群，心理社会压力和严重哮喘相关的固有专业知识的基础上。我们的提议包括少数民族健康中心（Center for Minority Health）的参与，该中心在少数民族人口的外展方面具有专业知识，凯斯西保留地彩虹婴儿中心（Rainbow Babies）的合作伙伴，以及匹兹堡阿勒格尼综合医院（Allegheny General Hospital）的卫星医院。第一项临床试验将比较两种已批准用于治疗成人发病哮喘表型的药物，该试验假设5-脂氧合酶抑制剂将比白三烯受体拮抗剂更有效。第二项研究评估了种族与社会经济地位对儿童皮质类固醇（CS）反应的作用，认为非裔美国人的哮喘表型，无论是否考虑社会经济地位，都预示着哮喘儿童对吸入性CS的不良反应。补充维生素D将克服不良反应并改善结果。我们将招募按种族和社会经济地位分层的非裔美国人和白人儿童。初步稳定后仍有症状的儿童将接受高剂量ICS治疗并确定疗效。所有没有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更好或相同程度地改善恶化和CS反应性。机制辅助方案将解决CS无反应性的各个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对改善它们的作用。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CRTH2的相互作用。我们相信这些研究解决了哮喘未被满足的需求，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.