Molecular Phenotyping of Asthma

描述（由申请人提供）：虽然哮喘通常被认为是一种单一疾病，但我们最近的数据表明并非所有哮喘都是相同的。这些观察结果表明，可以通过针对特定患者群体的特定治疗来改善哮喘治疗。不幸的是，我们目前还没有方法来区分这些不同的患者群体。这项拨款的总体目标是开发新的方法来识别这些哮喘患者群体。我们建议通过三种方法来做到这一点：1)区分不同类型的潜在炎症的患者，2)区分气道慢性结构变化（重塑）的患者和没有这种变化的患者，3)区分吸入皮质类固醇反应良好的患者和没有反应的患者。一些患者可能由于白细胞介素-13 （IL13）过度活跃引起的过敏性炎症而患有哮喘，白细胞介素-13是一种明显导致小鼠哮喘样疾病的生物介质。事实上，IL13的特异性阻滞剂正在被开发用于治疗哮喘。然而，我们的数据显示，只有一半的哮喘患者IL13活性过高，目前还没有办法区分这些患者。因此，这项资助的首要目标是通过使用基因表达微阵列研究患者肺组织和血液中基因的表达，开发“IL13驱动”哮喘的标志物。这些结果将有助于针对那些将受益的人进行il - 13阻断治疗。一些哮喘患者有慢性气道结构改变，称为气道重塑。这种重塑被认为会导致慢性气道狭窄。然而，目前不可能在没有活检的情况下确定谁有重塑。在这项资助的目标2中，我们建议使用一种称为“立体学”的技术来测量活组织检查中的重塑，并根据肺和血液中的基因表达来识别重塑的标记。我们相信这些结果将为研究患者气道重塑建立更好的方法，并将确定导致重塑的基因。最后，一些哮喘患者对吸入皮质类固醇治疗有很好的反应，而另一些则没有。人们对其原因了解甚少，而且很难预测谁会作出反应。此外，吸入皮质类固醇反应不佳的患者可能难以管理。在本资助的目标3中，我们建议通过将基因表达微阵列应用于肺和血细胞，作为吸入类固醇的2项临床试验的一部分，来确定哮喘患者对吸入皮质类固醇的反应标记。这些结果将有助于识别对皮质类固醇有耐药性的患者。他们还将确定有助于类固醇抗性的基因。事实上，在这些目标中，我们发现的标记物也可能是炎症、重塑、皮质类固醇抵抗的原因，而这些正是一些哮喘患者所遭受的。因此，除了在人类受试者中进行的研究外，我们建议使用细胞培养模型来研究这些基因是否会导致这些问题。这些细胞培养研究的最终目标是确定哮喘的新疗法。（摘要结束）

DESCRIPTION (provided by applicant): Although asthma is typically thought of as a single disease, our recent data suggest that not all asthma is the same. These observations suggest that asthma treatment could be improved by targeting specific therapies to the specific groups of patients that will respond to them. Unfortunately, we do not currently have methods to distinguish these different groups of patients. The overall goal of this grant is to develop novel methods to identify these groups of patients with asthma. We propose to do this in three ways, by developing methods to: 1) distinguish patients with different types of underlying inflammation, 2) distinguish patients with chronic structural changes in the airway (remodeling) from those without such changes and 3) distinguish patients who will respond well to inhaled corticosteroids from those who will not. Some patients may have asthma due to allergic inflammation caused by over-activity of interleukin-13 [IL13], a biological mediator that clearly causes an asthma-like condition in mice. Indeed, specific blockers of IL13 are being developed as a therapy for asthma. However, our data show that only half of patients with asthma have over activity of IL13, and currently there is no way to distinguish which patients these are. Therefore, the first aim of this grant is to develop markers of "IL13 driven" asthma by studying the expression of genes in lung tissue and blood of patients using gene expression microarrays. The results will help target IL13 blocking therapy to those who will benefit. Some patients with asthma have chronic structural changes in the airway known as airway remodeling. This remodeling is thought to cause chronic airway narrowing. However, it is currently impossible to determine who has remodeling without a biopsy. In aim 2 of this grant, we propose to measure remodeling in biopsies using a technique called "stereology" and identify markers of remodeling based on gene expression in the lung and blood. We believe the results will establish better methods for studying airway remodeling in patients and will identify genes that cause remodeling. Finally, some patients with asthma respond very well to inhaled corticosteroid therapy, whereas others do not. The reasons for this are poorly understood and it is difficult to predict who will respond. Furthermore, patients who do not respond well to inhale corticosteroids can be difficult to manage. In aim 3 of this grant we propose to identify markers of response to inhaled corticosteroids in asthma by applying gene expression microarrays to lung and blood cells as part of 2 clinical trials of inhaled steroids. These results will help identify patients who are resistant to corticosteroids. They will also identify genes that contribute to steroid resistance. Indeed, in each of these aims, the markers that we identify may also be causes of the inflammation, remodeling, corticosteroid resistance from which some patients with asthma suffer. Therefore, in addition to studies performed in human subjects, we propose to use cell culture models to study whether these genes can cause these problems. The ultimate goal of these cell culture studies is to identify new therapies for asthma. (End of Abstract)