Severe Asthma and the Glucocorticoid Receptor Complex

描述(申请人提供)：严重哮喘通常被定义为对持续大剂量吸入或口服类固醇控制炎症(类固醇抵抗)的反应不佳的慢性疾病。显然，存在多种类型的激素抵抗型哮喘，这可能是由于糖皮质激素受体介导的基因表达改变、糖皮质激素受体类固醇结合亲和力的差异或控制糖皮质激素受体复合体组装和功能的其他成分的缺陷所致。糖皮质激素受体(GR)只是大型多蛋白复合体的一部分。除了GR，构成最小的类固醇结合复合体还需要5种蛋白质成分，包括热休克蛋白90(HSP90α和β)、热休克蛋白70(hsc70和HSP70[1A和1B])、热休克蛋白40(Hsp40)、热休克组织蛋白(HSP)和p23。这8种蛋白的活性GR复合体的正确组装所需的基因将在一组严重哮喘患者中重新测序，以确定用于遗传关联研究的多态，并确定是否存在对这些蛋白的表达和/或翻译具有重要功能影响的多态。在确定这些多态性后，将对轻度和中度哮喘患者进行基因分型，以比较等位基因、基因型和单倍型频率以及组织炎症标志物和生理数据与重度哮喘患者的差异。这种基因分析的“途径”方法将是对严重哮喘人群中GR复合体的第一次也是最彻底的剖析。这项研究收集的信息将确定GR复合体与重症哮喘患者的皮质类固醇不敏感之间是否存在关联，并可能提供重要的遗传标记，可以预测哮喘患者对皮质类固醇治疗的反应(药物遗传学)。这也将为未来利用GR复合蛋白中识别的编码序列变体进行功能研究奠定基础。

DESCRIPTION (provided by applicant): Severe asthma is generally defined as a chronic condition with suboptimal response to continuous high-dose inhaled or oral steroids to control inflammation (steroid resistance). It is clear that many types of steroidresistant asthma exist, which may be explained by altered glucocorticoid receptor mediated gene expression, differences in glucocorticoid receptor steroid binding affinity, or defects in other components that control assembly and function of the glucocorticoid receptor complex. The glucocorticoid receptor (GR) is only one part of a large multi-protein complex. In addition to GR, five other protein components are necessary to constitute a minimum steroid binding complex, and include heat shock protein 90 (hsp90 alpha and beta), heat shock protein 70 (hsc70 and hsp70 [1A and 1B]), heat shock protein 40 (hsp40), hsp organizing protein (hop), and p23. Genes for these eight proteins required for proper assembly of an active GR complex will be re-sequenced in a population of severe asthmatics to define polymorphisms for use in genetic association studies and determine if there are polymorphisms which may have important functional effects on expression and/or translation of these proteins. After defining these polymorphisms, mild and moderate asthmatics will be genotyped to compare allele, genotype, and haplotype frequencies and differences in tissue inflammatory markers and physiological data with that of severe asthmatics. This "pathway" approach to genetic analysis will be the first and most complete dissection of the GR complex in a severe asthma population. Information gathered in this study will determine if there is an association between the GR complex and corticosteroid insensitivity in severe asthmatics and potentially provide important genetic markers that could predict how asthmatics may respond to administration of corticosteroids (pharmacogenetics). This will also lay the ground work for future functional studies using coding sequence variants identified in the GR complex proteins.