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.

该项目的目标是确定哮喘发病的新机制，以及严重疾病患者的新治疗方法。该项目将利用过敏性哮喘的小鼠模型来实现这些目标。 不同的皮质类固醇不反应基因组调节对皮质类固醇治疗无效的严重哮喘的疾病严重程度。我们推测，糖皮质激素不敏感基因的识别可能会为疾病发病机制提供新的见解，并为哮喘患者找到新的治疗方法。对临床相关的屋尘螨(HDM)哮喘激发模型的肺转录组进行全基因组图谱分析发现，载脂蛋白E(ApoE)的表达上调，尽管接受皮质类固醇治疗，载脂蛋白E的表达仍持续升高。这导致了载脂蛋白E低密度脂蛋白受体(LDLR)通路被确认为哮喘AHR和杯状细胞增殖的内源性负调节因子(载脂蛋白E通过低密度脂蛋白受体介导的途径负向调节屋尘螨诱导的哮喘)。姚X，弗雷德里克森·K，于正欣，徐翔，拉加瓦查里·N，基兰·KJ，Zywicke GJ，Kwak M，Amar MJ，Remaley AT，Levine SJ。Am J Respir CRUT CARE Med。2010年7月9日，印刷前的ePub)。特别是，我们发现apoE由肺巨噬细胞表达，并通过依赖低密度脂蛋白受体的机制负向调节气道高反应性和杯状细胞的增殖。此外，我们还发现这些作用是通过纤毛呼吸道上皮细胞表达的低密度脂蛋白受体来实现的。 这项对哮喘患者肺转录组的全基因组分析发现了更多对类固醇不敏感的基因，这些基因在哮喘中起着未知的作用。正在进行的研究正在利用这些候选皮质类固醇不反应基因的靶向缺失的小鼠来确定这些候选基因在哮喘发病机制中的作用。