Identifying and Characterizing "Corticosteroid-unresponsive" Genes in Asthma

该项目的目标是确定哮喘发病机制的新机制，以及严重疾病患者的新治疗方法。 该项目将利用小鼠过敏性哮喘模型来实现这些目标。 不同的皮质类固醇无反应基因组调节皮质类固醇治疗无效的严重哮喘的疾病严重程度。 我们假设，皮质类固醇无反应基因的鉴定可能 为疾病发病机制提供新的见解，并确定新的治疗方法 哮喘患者的治疗方法。 肺的全基因组分析 来自临床相关的屋尘螨（HDM）激发哮喘模型的转录组鉴定了载脂蛋白E（apoE）的上调表达， 尽管用皮质类固醇治疗，其仍然持续升高。 这导致鉴定出apoE LDL受体（LDLR）途径作为内源性的LDL受体通路。 哮喘中AHR和杯状细胞增生的负调节因子（载脂蛋白E通过LDL受体介导的负调节屋尘螨诱导的哮喘） 通路 Yao X，Fredriksson K，Yu ZX，Xu X，Raghavachari N，Keiden KJ，Zywicke GJ， Kwak M，Amar MJ，Remaley AT，Levine SJ. Am J Respir Crit Care Med. 2010年7月9日。 Epub before print）。 特别是，我们发现apoE由肺巨噬细胞表达，并通过LDL受体依赖性机制负调节气道高反应性和杯状细胞增生。 此外，我们发现这些作用是通过纤毛气道上皮细胞表达的LDL受体介导的。 这项对哮喘患者肺转录组的全基因组分析已经确定了额外的类固醇无反应基因，这些基因在哮喘中的作用尚不清楚。 正在进行的研究使用这些候选皮质类固醇无反应基因的靶向缺失小鼠来确定这些候选基因在哮喘发病机制中的作用。

This project that has the goal of identifying novel mechanisms of asthma pathogenesis, as well as new treatment approaches for patients with severe disease. The project will utilize murine models of allergic asthma to achieve these goals. Distinct sets of corticosteroid-unresponsive genes modulate disease severity in severe asthma that is refractory to corticosteroid therapy. We hypothesized that the identification of corticosteroid-unresponsive genes may provide new insights into disease pathogenesis and identify novel therapeutic approaches for asthmatic patients. Genome-wide profiling of the lung transcriptome from a clinically relevant, house dust mite (HDM) challenge model of asthma identified the up-regulated expression of apolipoprotein E (apoE), which remained persistently elevated despite treatment with corticosteroids. This lead to the identification of an apoE LDL receptor (LDLR) pathway as an endogenous negative regulator of AHR and goblet cell hyperplasia in asthma (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). In particular, we showed that apoE is expressed by lung macrophages and negatively regulates airway hyperreactivity and goblet cell hyperplasia via a LDL receptor-dependent mechanism. Furthermore, we showed that these effects are mediated via LDL receptors that are expressed by ciliated airway epithelial cells. This genome-wide analysis of the lung transcriptome in asthma has identified additional steroid-unresponsive genes that are not known to have a role in asthma. Ongoing studies are using mice with targeted deletions in these candidate corticosteroid-unresponsive genes to define the role of these candidate genes in the pathogenesis of asthma.