The Role of RIP2 Kinase in the Pathogenesis of Allergic Asthma

描述(申请人提供)：最广泛使用的哮喘治疗方法包括支气管扩张剂和吸入皮质类固醇。尽管大多数哮喘患者通过这些药物的某种组合来实现控制，但也有一些人从这些治疗中得不到任何好处，而且几乎没有其他治疗方法可供选择。这表明有必要开发新的哮喘治疗方法。尽管已经开发了许多针对哮喘治疗的生物制剂，但很少有生物制剂转化为临床(白三烯修饰物2，3和抗IgE4，5)。在临床前模型中发现有效的治疗方法和那些对哮喘患者实际有益的治疗方法之间的差异，可能可以通过治疗所针对的过敏性哮喘反应的阶段来解释。许多这样的生物制剂，如抗IL-46，7，抗IL-58，和抗IL-139，10疗法，是针对在过敏反应后期产生的分子。通过研究过敏反应启动过程中发生的事件，我们可能会更好地理解并能够操纵免疫反应来获得临床收益。尽管我们知道下游过敏和哮喘的后遗症(细胞因子和炎症介质的释放导致粘液过度产生、呼吸道高反应性、上皮下纤维化等)，但关于哪些受体和信号通路在启动过敏反应中起重要作用尚不清楚。核苷酸寡聚化结构域2(NOD2)是肽聚糖11-13的一种天然免疫受体，最近也参与了2型反应14-16的发生。当这种反应失调时，它们会促进过敏性和哮喘疾病的发展。RIP2是从NOD217、18发出的信号传导中必不可少的一种激酶。通过确定RIP2在对变应原的初始反应中所起的作用并确定影响RIP2活性的新机制，人们可以确定抑制RIP2是否可以有效地治疗过敏性哮喘。目前的建议试图通过使用遗传和生化RIP2激活标记来确定RIP2激活是否发生在过敏原暴露的下游。我们还将探索一种新的机制，通过它可以潜在地激活RIP2(非依赖于NOD)，以及这可能如何有助于哮喘的发病机制。最后，通过利用一种新的RIP2过度激活环境(发痒的小鼠)和新的RIP2抑制剂，我们将确定RIP2抑制在哮喘动物模型中的有效性。

DESCRIPTION (provided by applicant): The most widely used treatments for asthma consist of bronchodilators and inhaled corticosteroids. Although majority of asthmatics achieve control with some combination of these medications, there are those who receive no benefit from these treatments1 and for whom few alternative treatments remain. This indicates the need for the development of novel asthma therapies. Despite the numerous biologic agents developed which are targeted for the treatment of asthma, few have translated into the clinic (leukotriene modifiers2, 3 and anti- IgE4, 5). This disparity between what therapies are found to be efficacious in preclinical models and those which are actually beneficial in asthmatics, might be explained by the stage in the allergic asthmatic response being targeted by the therapy. A number of these biologicals such as anti-IL-46, 7, anti-IL-58, and anti-IL-139, 10 therapy, are directed at molecules which are generated late in the allergic reaction. By studying events which occur during the initiation of an allergic response, we might better understand and be able to manipulate immune responses for clinical gain. In spite of our knowledge of the downstream allergic and asthmatic sequelae (release of cytokines and inflammatory mediators leading to mucus overproduction, airway hyperreactivity, subepithelial fibrosis etc), little is known about which receptors and signaling pathways are important in initiating an allergic response. Nucleotide Oligomerization Domain 2 (NOD2) is an innate immune receptor for peptidoglycan11-13 which has also recently been implicated in the development of type-2 responses14-16. When such responses are dysregulated, they can promote the development of allergic and asthmatic disease. RIP2 is a kinase which is essential for transducing signals emanating from NOD217, 18. By determining the role which RIP2 plays during the initial response to allergens and identifying novel mechanisms by which RIP2 activity is influenced, one can ascertain if inhibition of RIP2 may be efficacious for the treatment of allergic asthma. The current proposal seeks to determine if RIP2 activation occurs downstream of allergen exposure through the use of genetic and biochemical RIP2 activation markers. We will also explore a novel mechanism by which RIP2 can potentially be activated (NOD independent) and how this may contribute to the pathogenesis of asthma. Lastly, by utilizing a novel setting of RIP2 overactivation (the Itchy mouse) and novel RIP2 inhibitors, we will determine the efficacy of RIP2 inhibition in animal models of asthma.