Identifying and Characterizing "Corticosteroid-unresponsive" Genes in Asthma

哮喘中“皮质类固醇无反应”基因的识别和特征分析

• 批准号: 8557924
• 负责人: Stewart Levine
• 金额: $ 45.58万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8557924
• 关键词: Accounting; Adrenal Cortex Hormones; Apolipoprotein E; Asthma; Breathing; Candidate Disease Gene; Caring; Disease; Dose; Emergency treatment; Epithelial Cells; Extrinsic asthma; Gene Expression Profile; Genes; Goals; Goblet Cells; Health Care Costs; Health Expenditures; Hospitalization; Hyperplasia; Lead; Low Density Lipoprotein Receptor; Lung; Mediating; Modeling; Morbidity - disease rate; Mus; Obstruction; Oral; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Prevalence; Printing; Public Health; Pyroglyphidae; Refractory; Role; Severity of illness; Steroids; United States; Visit; airway hyperresponsiveness; asthma inhaler; asthmatic patient; attributable mortality; clinically relevant; disorder control; genome-wide; genome-wide analysis; high risk; insight; macrophage; mortality; novel; novel therapeutic intervention

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.

该项目的目的是确定哮喘发病机理的新机制，以及针对严重疾病患者的新治疗方法。 该项目将利用过敏性哮喘的鼠模型来实现这些目标。 不同的皮质类固醇非反形基因调节严重哮喘的疾病严重程度，这对皮质类固醇治疗难治性。 我们假设鉴定皮质类固醇非震源基因可能会为疾病发病机理提供新的见解，并确定哮喘患者的新型治疗方法。 肺部尘螨（HDM）哮喘挑战模型的肺转录组的全基因组分析鉴定出载脂蛋白E（APOE）的上调表达，尽管皮质类固醇治疗了，但该模型仍持续升高。 这导致哮喘中APOE LDL受体（LDLR）途径是AHR和Goblet细胞增生的内源性负调节剂（载脂蛋白E负调节房屋灰尘螨虫通过LDL受体介导的途径，从而通过LDL受体介导的途径进行了尘埃诱导的哮喘。 KJ，Zywicke GJ，Kwak M，Amar MJ，Remaley at Levine SJ。 特别是，我们表明APOE通过肺巨噬细胞表达，并通过LDL受体依赖性机制对气道高反应性和杯状细胞增生进行负调节。 此外，我们表明这些作用是通过纤毛气道上皮细胞表达的LDL受体介导的。 对哮喘中肺转录组的全基因组分析已经鉴定出了其他类固醇 - 无抗反应基因，这些基因在哮喘中不起作用。 正在进行的研究正在使用这些候选皮质类固醇无反抗基因中具有靶向缺失的小鼠来定义这些候选基因在哮喘发病机理中的作用。