Targeting Sphingosine and Ceramide Kinases and Inflammation

肥大细胞协调炎症细胞的募集并启动和维持过敏反应 通过它们释放多种炎症介质的能力，包括组胺和其他 预先形成的介质，从头合成的花生四烯酸代谢物（白三烯和 和许多促炎细胞因子和趋化因子。所有这些都被证明可以发挥作用 在哮喘的发病机制及其加重中起重要作用。我们最近的研究已经开始 暗示了有效的鞘脂代谢物，鞘氨醇-1-磷酸（S1 P）和神经酰胺-1-磷酸 (C1P)以及产生它们的激酶，鞘氨醇激酶（SphK 1和SphK 2）和神经酰胺激酶 （CerK），分别在调节肥大细胞的脱粒和它们的趋化因子分泌中， 细胞因子和类花生酸合成（特别是PGD 2和CysLT）。该提案旨在加强 了解这些鞘脂代谢物和调节其水平的酶在体内的作用， 人肥大细胞在过敏反应和哮喘中的功能。在目标1中，我们将研究 S1 P受体、SphKs和CerK在放大和维持人肥大细胞过敏反应中的作用 目的2集中于确定S1 P如何由人肥大细胞分泌。在目标3中，我们将确定 靶向类花生酸产生的SphKs和FTY 720类似物的新型抑制剂的有效性， 对人类肥大细胞功能的影响在目标4中，我们将确定这些新型抑制剂在以下方面的有效性： 减轻小鼠哮喘模型中的气道高反应性。这些研究将进一步促进我们的 了解S1 P和C1 P在协调人类肥大细胞功能和免疫中的关键作用 反应，为开发靶向调节酶的治疗剂提供基础。 他们的水平和“铺平道路”的发展，有效的和具体的药物，可能是 可用于治疗患者的哮喘。

Mast cells orchestrate the recruitment of inflammatory cells and initiate and perpetuate allergic responses through their ability to release a wide array of inflammatory mediators, including histamine and other preformed mediators, de novo synthesized arachidonic acid metabolites (leukotrienes and prostaglandins), and numerous proinflammatory cytokines and chemokines. All have been shown to play important roles in the pathogenesis of asthma and its exacerbation. Our recent studies have begun to implicate the potent sphingolipid metabolites, sphingosine-1 -phosphate (S1P) and ceramide-1 -phosphate (C1P) and the kinases that produce them, sphingosine kinases (SphK1 and SphK2) and ceramide kinase (CerK), respectively, in regulation of degranulation of mast cells and their secretion of chemokines and cytokines, and eicosanoid synthesis (particularly PGD2 and CysLT). This proposal is aimed at enhancing understanding of the roles of these sphingolipid metabolites and the enzymes that regulate their levels in human mast cell functions in allergic responses and asthma. In Aim 1, we will examine the involvement of S1P receptors, SphKs, and CerK in amplifying and perpetuating allergic responses of human mast cells. Aim 2 is focused on determining how S1P is secreted by human mast cells. In Aim 3, we will determine the effectiveness of novel inhibitors of SphKs and FTY720 analogues that target eicosanoid production, on human mast cell functions. In Aim 4, we will determine the effectiveness of these novel inhibitors in alleviation of airway hyper-responsiveness in murine asthma models. These studies will further our understanding of the critical role of S1P and C1P in orchestrating human mast cell functions and immune reactions, providing the basis for development of therapeutic agents that target the enzymes that regulate their levels and "pave the way" for the development of potent and specific drugs that potentially could be useful for treating asthma in patients.