Novel strategies for asthma therapy by regulating mast cell signaling by MyD88

描述（由申请人提供）：哮喘是一种复杂的气道炎症性疾病，以支气管收缩、气道高反应性和炎症为特征。有大量证据表明肥大细胞高亲和IgE受体（FceRI）在哮喘发病机制中起重要作用。因此，对该受体功能调控的信号通路的理解已经付出了巨大的努力。越来越多的证据表明，上皮细胞来源的细胞因子如白细胞介素-33 （IL-33）和细菌脂多糖（LPS）通过激活各自的受体ST2和TLR4在哮喘加重中发挥重要作用，但其作用机制尚不清楚。髓样分化因子（Myeloid differentiation factor, MyD） 88是距离IL-33和LPS信号传递最近的适配分子。我们发现MyD88不仅调节肥大细胞中的IL-33和LPS信号，还参与抗原/ ige介导的蛋白激酶B （Akt）磷酸化和细胞因子的产生。我们还发现LPS或IL-33与抗原/IgE协同产生细胞因子，并且这种串音在MyD88-/-肥大细胞中几乎被消除。基于这些发现，我们假设MyD88通过调节和交叉调节肥大细胞中的Fc5RI信号传导来促进过敏性炎症。进一步探讨MyD88在体外肥大细胞信号传导和体内小鼠变应性炎症模型中的作用有两个具体目的。在目标1中，我们将使用逆转录病毒转染野生型或转基因MyD88的MyD88-/-肥大细胞，以描述该适配器分子如何调节和交叉调节肥大细胞中的FceRI信号传导。在目标2中，我们将首先验证肥大细胞中表达的MyD88介导体内过敏性炎症的假设。然后，我们将调节肥大细胞中的MyD88信号，并确定这种调节对过敏性炎症的影响。我们相信，这些研究将为肥大细胞中FceRI信号的调控和交叉调控提供重要的新信息，并可能为哮喘和其他过敏性疾病的治疗提供新的治疗方法。公共卫生相关性：哮喘是一种复杂的气道炎症性疾病，以支气管收缩、气道高反应性和炎症为特征。估计大约有1700万美国人患有哮喘，其中三分之一是儿童。近年来，哮喘的患病率和严重程度在世界范围内急剧增加。肥大细胞释放炎症介质，引起哮喘和其他过敏性疾病的症状。这一建议是基于一种调节肥大细胞功能的新分子的鉴定。我们相信，拟议的研究将产生关于肥大细胞功能调节的重要新信息，并可能为哮喘和其他过敏性疾病的治疗提供新的治疗方法。

DESCRIPTION (provided by applicant): Asthma is a complex airway inflammatory disease characterized by bronchoconstriction, airway hyperresponsiveness and inflammation. There is a substantial body of evidence that demonstrates an important role for mast cell high affinity IgE receptor (FceRI) in the pathogenesis of asthma. Therefore, tremendous efforts have been directed towards understanding the signaling pathway via which function of this receptor is regulated. Emerging evidence suggests that epithelial cell-derived cytokine such as interleukin-33 (IL-33) and bacterial lipopolysaccharide (LPS) play important roles in asthma exacerbation via the activation of their respective receptors ST2 and TLR4 but the mechanisms of their action remains unknown. Myeloid differentiation factor (MyD) 88 is the most proximal adapter molecule that transmits signal for both IL-33 and LPS. We made the novel observation that MyD88 not only regulates IL-33 and LPS signaling in mast cells, it also contributes to antigen/IgE-mediated protein kinase B (Akt) phosphorylation and cytokine production. We also found that LPS or IL-33 synergizes with antigen/IgE for cytokine generation and that this cross-talk is almost abolished in MyD88-/- mast cells. Based on these findings, we hypothesize that MyD88 promotes allergic inflammation by regulating and cross-regulating Fc5RI signaling in mast cells. Two specific aims are proposed to further explore the role of MyD88 on mast cell signaling in vitro and murine model of allergic inflammation in vivo. In aim #1, we will use retrovirus to transfect MyD88-/- mast cells with wild-type or genetically modified MyD88 to delineate how this adapter molecule regulates and cross-regulates FceRI signaling in mast cells. In aim #2, we will first test the hypothesis that MyD88 expressed in mast cells mediates allergic inflammation in vivo. We will then modulate MyD88 signaling in mast cells and determine the impact of this modulation on allergic inflammation. We believe that proposed studies will generate significant new information on the regulation and cross-regulation of FceRI signaling in mast cells and may offer novel therapeutic approaches for the treatment of asthma and other allergic diseases. PUBLIC HEALTH RELEVANCE: Asthma is a complex airway inflammatory disease characterized by bronchoconstriction, airway hyperresponsiveness and inflammation. Approximately 17 million Americans are estimated to have asthma, one third of them children. In recent years, asthma prevalence and severity have been increasing dramatically world-wide. Mast cells release inflammatory mediators that cause the symptoms of asthma and other allergic diseases. This proposal is based on the identification of a new molecule that regulates mast cell function. We believe that proposed studies will generate significant new information on the regulation of mast cell function and may offer novel therapeutic approaches for the treatment of asthma and other allergic diseases.