Targeting Sphingosine and Ceramide Kinases and Inflammation

靶向鞘氨醇和神经酰胺激酶和炎症

基本信息

批准号：
7476204
负责人：
SARAH SPIEGEL
金额：
$ 20.96万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7476204
关键词：
ATP-Binding Cassette Transporters Affinity Agonist Allergic Allergic Reaction Antigens Arachidonic Acids Asthma Cell Degranulation Cell Surface Receptors Cell physiology Cell secretion Cells Chronic Complement Cytosolic Phospholipase A2 Development Disease Down-Regulation Effectiveness Eicosanoid Production Eicosanoids Enzymes Eosinophilia Event Family Figs - dietary Generations H218 Protein HTATIP gene Histamine Human IgE IgE Receptors Immune Immune response Immunosuppressive Agents Inflammation Inflammatory Inflammatory Response Inhibitory Concentration 50 Interleukin-6 Isoenzymes Leukotrienes Link Lipids Location Lung Inflammation Lymphocyte Lymphoid Mediating Mediator of activation protein Modeling Molecular Movement Mus NF-kappa B Organ PLA2G4A gene PTGS2 gene Pathogenesis Patients Pharmaceutical Preparations Phosphotransferases Play Production Prostaglandin D2 Prostaglandins Reaction Regulation Rodent Role Scheme Signal Transduction Site Small Interfering RNA Sphingolipids Sphingosine Sphingosine-1-Phosphate Receptor Testing Therapeutic Agents Transactivation Work airway hyperresponsiveness analog autocrine base cell motility cell type ceramide 1-phosphate ceramide kinase chemokine crosslink cysteinyl-leukotriene cytokine human PLA2G4A protein in vivo inhibitor/antagonist interest lipid transport mast cell migration mimetics novel paracrine prevent receptor response small molecule sphingosine 1-phosphate sphingosine kinase

项目摘要

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.

肥大细胞协调炎症细胞的募集，并启动和永久性过敏反应通过释放各种炎症介质的能力，包括组胺和其他预先形成的介体，从头合成的花生四烯酸代谢产物（白细胞和白细胞代谢产物）前列腺素）以及许多促炎细胞因子和趋化因子。所有这些都被证明在哮喘的发病机理及其加重中的重要作用。我们最近的研究开始暗示有效的鞘脂代谢物，鞘氨醇1-磷酸（S1P）和神经酰胺-1-磷酸盐（C1P）和产生它们的激酶，鞘氨酸激酶（SPHK1和SPHK2）和神经酰胺激酶（CERK）分别在调节肥大细胞脱粒的调节及其分泌趋化因子和它们的分泌方面细胞因子和类花生酸合成（尤其是PGD2和CYSLT）。该建议旨在增强了解这些鞘脂代谢产物的作用和调节其水平的酶人类肥大细胞在过敏反应和哮喘中起作用。在AIM 1中，我们将研究 S1P受体，SPHK和CERK在扩增和永久的人肥大细胞过敏反应中。 AIM 2的重点是确定S1P是如何被人类肥大细胞分泌的。在AIM 3中，我们将确定靶向类eicosanoid的新型SPHK和FTY720类似物的新型抑制剂的有效性，在人类肥大细胞功能上。在AIM 4中，我们将确定这些新颖抑制剂在在鼠哮喘模型中缓解气道高反应性。这些研究将进一步了解S1P和C1P在编排人类肥大细胞功能和免疫的关键作用反应，为靶向调节酶的治疗剂的开发提供了基础它们的水平并为开发有效和特定药物的开发而“铺平道路”可能是可用于治疗患者哮喘。