MECHANISMS OF CORTICOSTEROID RESISTANT ASTHMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究的目的是了解区分“皮质激素抵抗”(CR)和“皮质激素敏感”(CS)哮喘的免疫学和分子机制。有四个具体的研究目标：第一，为了研究细胞因子在激素抵抗发病机制中的作用，我们将确定缓解性哮喘患者的外周血单个核细胞(PBMC)和BAL细胞是否比CS哮喘患者的细胞产生更高水平的IL-2、IL-4和IL-13。第二，通过体外丝裂原驱动的地塞米松反应不敏感来评估外周血T细胞的皮质类固醇抵抗是否是严重哮喘的标志，以及非裔美国哮喘患者是否比其他种族人群有更高的皮质类固醇抵抗患病率。第三，为了明确细胞因子诱导类固醇抵抗的机制(S)，我们将检测CR哮喘患者、CS哮喘患者和正常对照的支气管肺泡灌洗液细胞和PBMC中糖皮质激素受体β和GCRα。我们还将确定GCRα异源二聚体形成的细胞内位置。最后，我们将建立CR和CS个体的DNA库，以确定与NIH赞助的药物遗传学研究网络研究小组合作确定的DNA序列变异是否与皮质类固醇耐药有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this research project are to understand the immunologic and molecular mechanisms which distinguish "corticosteroid resistant" (CR) from "corticosteroid sensitive" (CS) asthma. Four specific aims are being pursued: First, to examine the role of cytokines in the pathogenesis of corticosteroid resistance, we will determine whether peripheral blood mononuclear cells (PBMC) and BAL cells from patients with CR asthma produce higher levels of IL-2, IL-4 and IL-13 than cells from patients with CS asthma. Second, to determiine whether peripheral blood corticosteroid resistance of T cells assessed by insensitivity of in vitro mitogen-driven responses to dexamethasone is a marker for severe asthma and if African-American asthmatics have a higher prevalence of corticosteroid resistance than other ethnic groups. Third, to identify the mechanisms(s) by which cytokines induce steroid resistance, we will evaluate glucocorticoid receptor (GCR) Beta and GCR Alpha in bronchoalveolar lavage (BAL) cells and PBMC from CR asthmatics, CS asmatics and normal controls. We will also define the intracellular location of GCR Alpha heterodimer formation. Finally, we will establish a bank of DNA from CR and CS individuals for the purpose of determining whether DNA sequence variants, identified in collaboration with a NIH-sponsored Pharmacogenetic Research Network Research Group, are associated with corticosteroid resistance.