Targeting Sphingosine and Ceramide Kinases and Inflammation

肥大细胞协调炎症细胞的募集，启动和维持过敏反应 通过它们释放广泛的炎症介质的能力，包括组胺和其他 预制介体，从头合成的花生四烯酸代谢物(白三烯和 前列腺素)，以及许多致炎细胞因子和趋化因子。所有的人都已经表演过了 在哮喘及其加重的发病机制中起着重要作用。我们最近的研究已经开始 涉及有效的鞘磷脂代谢物，鞘氨醇-1-磷酸(S1P)和神经酰胺-1-磷酸 (C1P)和产生它们的激酶，鞘氨醇激酶(SphK1和SphK2)和神经酰胺酶 (Cerk)分别在调节肥大细胞脱颗粒及其趋化因子和 细胞因子和二十烷类化合物的合成(特别是PGD2和CysLT)。这项建议旨在加强 了解这些鞘磷脂代谢物的作用以及调节其水平的酶在 人类肥大细胞在过敏反应和哮喘中的作用。在目标1中，我们将研究 S1P受体、SphKs和Cerk在放大和维持人肥大细胞过敏反应中的作用。 目标2的重点是确定人类肥大细胞如何分泌S1P。在目标3中，我们将确定 针对二十烷类化合物生产的SphKs和FTY720类似物的新型抑制剂的有效性， 人类肥大细胞的功能。在目标4中，我们将确定这些新型抑制剂在 减轻小鼠哮喘模型的气道高反应性。这些研究将进一步推动我们的 理解S1P和C1P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了基础 它们的水平，并为开发有效和特定的药物铺平了道路，这些药物可能 对治疗哮喘患者很有用。

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.