Treatment of Asthma by Targeting JAK3 with JANEX-1

描述（由申请人提供）：大约有5000万人患有哮喘和过敏症，其中500万人年龄在18岁以下。我们的核心工作假设是JAK3在过敏性哮喘的病理生理中起着核心作用，JAK3抑制剂可能通过抑制肥大细胞介质的释放和气道中嗜酸性粒细胞的募集来预防体内哮喘反应。为了验证这一假设，我们将使用具有良好特征的过敏性哮喘小鼠模型研究JAK3抑制剂JANEX-1的作用。具体来说，我们将在一个具有良好特征的过敏性哮喘小鼠模型中研究JANEX-1对抗原诱导的哮喘反应的强度和结果的影响。在变应性哮喘模型中，JANEX-1处理小鼠将检测其抗原诱导的早期（气道阻塞）和晚期哮喘反应、支气管高反应性和气道炎症。我们将研究：(i)使用JAK3抑制剂对小鼠进行慢性预处理（腹膜内和口服）是否可以防止抗原诱导的支气管高反应性和嗜酸性粒细胞募集。我们还将研究是否可以通过静脉注射JAK3抑制剂来消除持续的哮喘反应。此外，由于雾化药物是哮喘的最佳治疗策略，我们还将研究雾化JAK3抑制剂对小鼠过敏性哮喘的影响。为了评估炎症反应，还将估计支气管肺泡灌洗液中炎症介质（如IL-5、组胺、EPO、白三烯C4）的释放和炎症细胞（嗜碱性粒细胞、嗜酸性粒细胞、中性粒细胞）的流入。将JANEX-1处理和未处理小鼠的肺组织进行细胞浸润和病理改变检查。本研究的完成可能为过敏性哮喘的新型预防和治疗措施提供基础。

DESCRIPTION (provided by applicant): Approximately 50 million people suffer from asthma and allergies of which 5 millions are under the age of 18 years. It is our central working HYPOTHESIS that JAK3 plays a central role in the pathophysiology of allergic asthma and JAK3 inhibitors may be useful to prevent asthmatic responses in vivo by inhibiting the mast cell mediator release and recruitment of eosinophils in airways. To test this hypothesis we will study the effect of the JAK3 inhibitor JANEX-1 using a well-characterized mouse model of allergic asthma. Specifically, we will examine the effect of JANEX-1 on the magnitude and outcome of antigen-induced asthmatic reactions in a well-characterized mouse model of allergic asthma. In the allergic asthma model, JANEX-1 treated mice will be examined for their antigen-induced early (airway obstruction) as well as late phase asthmatic response, bronchial hyper-responsiveness and airway inflammation. We will examine if: (i) chronic pretreatment (intra-peritoneal as well as oral) of mice with JAK3 inhibitor can prevent antigen-induced bronchial hyper-responsiveness and eosinophil recruitment. We will also examine if ongoing asthmatic reaction can be abrogated by intravenous treatment with JAK3 inhibitors. Further, since aerosolized drugs provide best treatment strategy for asthma, we will also examine the effect of aerosolized JAK3 inhibitors on allergic asthma in mice. To assess the inflammatory response, release of inflammatory mediators (e.g. IL-5, histamine, EPO, leukotriene C4) and influx of inflammatory cells viz. (basophils, eosinophils, neutrophils) will also be estimated in bronchoalveolar lavage fluids. Lung tissue obtained from JANEX-1 treated and untreated mice will be examined for cellular infiltration and pathological changes. The completion of the proposed studies may provide the foundation for novel preventive and therapeutic measures against allergic asthma.