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的疾病，但我们最近的数据表明，并不是所有的哮喘都是一样的。这些观察表明，通过针对对哮喘有反应的特定患者群体进行特定的治疗，哮喘的治疗可以得到改善。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。这笔赠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，通过开发方法来：1)区分患有不同类型潜在炎症的患者，2)区分有慢性呼吸道结构变化(重塑)的患者和那些没有这种变化的患者，以及3)区分对吸入皮质类固醇有良好反应的患者和不能对其有良好反应的患者。一些患者可能患有哮喘，原因是白介素13[IL13]过度活动引起的过敏性炎症，白介素13是一种生物介质，显然会导致小鼠出现类似哮喘的情况。事实上，正在开发IL13的特定阻滞剂作为哮喘的治疗方法。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哪些患者是这些患者。因此，这笔拨款的第一个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的基因表达，开发由IL13驱动的哮喘的标记。这一结果将有助于将IL13阻断治疗的目标对准那些受益的人。一些哮喘患者的呼吸道有慢性结构变化，称为气道重塑。这种重塑被认为是导致慢性呼吸道狭窄的原因。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“体视学”的技术来测量活检组织中的重塑，并基于肺和血液中的基因表达来识别重塑的标志物。我们相信，这些结果将为研究患者的气道重塑建立更好的方法，并将识别导致重塑的基因。最后，一些哮喘患者对吸入皮质类固醇治疗反应很好，而另一些患者则不是。造成这种情况的原因人们知之甚少，也很难预测谁会做出回应。此外，吸入皮质类固醇反应不佳的患者可能很难管理。在这项赠款的目标3中，我们建议通过将基因表达微阵列应用于肺和血细胞来识别哮喘患者对吸入性皮质类固醇的反应标记物，作为吸入性类固醇临床试验的一部分。这些结果将有助于识别对皮质类固醇耐药的患者。他们还将识别导致类固醇耐药的基因。事实上，在这些目标中的每一个，我们识别的标志物也可能是一些哮喘患者遭受的炎症、重塑和皮质类固醇抵抗的原因。因此，除了在人类受试者身上进行的研究外，我们还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)