Targeting sphingosine kinases in FceRI-mediated allergic responses

描述(申请人提供)：肥大细胞通过其释放广泛的炎症介质，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(白三烯和前列腺素)，以及许多促炎细胞因子和趋化因子的能力，协调炎症细胞的招募，启动和持续过敏反应。所有这些都被证明在过敏性疾病的发病机制中发挥重要作用，如过敏反应和哮喘，以及它们的恶化。我们最近的研究已经开始涉及到强大的鞘氨醇代谢物-1-神经鞘氨醇-1-磷酸(S1P)和神经酰胺-1-磷酸(C1P)及其产生的激酶-鞘氨醇激酶(SphK1和SphK2)和神经氨酸激酶(CERK)分别调节肥大细胞脱颗粒及其趋化因子和细胞因子的分泌，以及二十烷类化合物的合成(特别是PGD2和CysLT)。这项建议旨在加强对这些鞘磷脂代谢物及其在人体肥大细胞功能中调节其水平的酶在过敏反应和过敏反应中的作用的了解。我们的假设是，SphK1(可能还有SphK2)是治疗过敏反应的新靶点，肥大细胞在其中发挥关键作用。在目标1中，我们将证实S1P和C1P及其调节其水平的酶在放大和维持人类肥大细胞的过敏反应中的参与。在目标2中，我们将确定新型抑制剂(针对产生S1P和C1P的激酶)和FTY720类似物对人类肥大细胞功能的抑制作用。目标3的重点是确定人类肥大细胞如何分泌S1P。最后，在目标4中，我们将确定在目标2中开发的新型抑制剂在减轻小鼠皮肤和全身过敏反应以及呼吸道高反应性方面的有效性。这些研究将进一步加深我们对S1P在协调人类肥大细胞功能和免疫反应中的关键作用的理解，为开发针对调节其水平的酶的治疗剂提供基础，并为开发可能有助于治疗各种严重的人类免疫反应(包括过敏反应和哮喘)的有效和特定的药物铺平道路。肥大细胞协调炎症细胞的募集，启动和维持过敏反应。公共卫生相关性：这项提案的重点是生物活性鞘脂代谢物在调节人类肥大细胞功能中的作用。鞘磷脂信号是人类过敏性疾病的核心，并有可能成为治疗靶点。拟议中的研究对过敏性疾病的治疗大有可为。

DESCRIPTION (provided by applicant): 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 allergic disorders, such as anaphylaxis and asthma, and their 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 anaphylaxis. It is our hypothesis that SphK1 (and possibly SphK2) are novel targets for the treatment of allergic responses in which mast cells play pivotal roles. In Aim 1, we will substantiate the involvement of S1P and C1P and the enzymes that regulate their levels in amplifying and perpetuating allergic responses of human mast cells. In Aim 2, we will determine the effectiveness of novel inhibitors (targeting the kinases producing S1P and C1P) and FTY720 analogues that block eicosanoid production on human mast cell functions. Aim 3 is focused on determining how S1P is secreted by human mast cells. Finally, in Aim 4, we will determine the effectiveness of the novel inhibitors developed in Aim 2 in alleviation of cutaneous and systemic anaphylaxis and airway hyper-responsiveness in murine models. These studies will further our understanding of the critical role of S1P in orchestrating human mast cell functions and immune reactions, providing the basis for development of therapeutic agents that target the enzymes that regulate its levels and "pave the way" for the development of potent and specific drugs that potentially could be useful for treating various severe human immune responses, including anaphylaxis and asthma. Mast cells orchestrate the recruitment of inflammatory cells and initiate and perpetuate allergic responses. Public Health Relevance: This proposal is focused on the role of bioactive sphingolipid metabolites in regulating functions of human mast cells. Sphingolipid signaling is central to human allergic diseases and potentially amenable to therapeutic targeting. The proposed studies hold much promise for treatment of allergic disorders.