Sphingosine Phosphate Role in Inflammation

磷酸鞘氨醇在炎症中的作用

基本信息

批准号：
7927827
负责人：
Lina M OBEID
金额：
$ 11.84万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7927827
关键词：
Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Automobile Driving Binding Biological Assay Blood Platelets Cell Line Cell Survival Cell model Cells Ceramidase Ceramides Complementary DNA Data Dinoprostone Dominant-Negative Mutation Enzymes Family Funding G-Protein-Coupled Receptors Generations Genes Goals Heart Homologous Gene Human Human Cloning IL2 gene Immunohistochemistry Inflammation Inflammatory Inflammatory Response Laboratories Lipids Lipopolysaccharides Lyase Mediating Metabolism Mitogen-Activated Protein Kinases Molecular Mus NF-kappa B Normal tissue morphology PTGS2 gene Pathway interactions Peritoneal Macrophages Phosphoric Monoester Hydrolases Phosphorylation Process Production Protein Dephosphorylation Proteins Regulation Research Personnel Role SPHK1 enzyme Saccharomyces cerevisiae Sampling Scheme Serum Small Interfering RNA Sphinganine-1-phosphate aldolase Sphingolipids Sphingosine Sphingosine-1-Phosphate Receptor Stimulation of Cell Proliferation Stimulus TNF gene Testing Tissues analog angiogenesis cell type cyclooxygenase 2 cytokine human tissue in vivo in vivo Model inorganic phosphate insight macrophage member novel novel therapeutic intervention overexpression programs receptor receptor binding release of sequestered calcium ion into cytoplasm response sphingosine 1-phosphate sphingosine kinase tool

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to define the role of the novel lipid pathway mediated by sphingosine-1- phosphate (S1P) in inflammation and to establish components of this pathway as potential novel targets for anti-inflammatory therapy. The PI's laboratory has an established track record of expertise in sphingolipid metabolism and function. Studies from the previous funding period have led us into a novel exciting direction on the role and regulation of S1P in inflammation. S1P is generated by phosphorylation by sphingosine kinase (SK) in many cell types including inflammatory cells. S1P acts extracellularly by binding to members of the G-protein coupled receptors S1P1-5, or intracellularly on poorly defined targets. It mediates several biologic activities, including mitogenesis, cell survival, angiogenesis and inflammatory responses. In this competing renewal we have compelling new data, whereby we have implicated this pathway as a key regulator of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. In addition we find that SK1 is significantly overexpressed in inflammatory tissues. We also demonstrate that bacterial lipopolysaccharide (LPS) regulates SK1. This proposal will therefore, test the hypothesis that SK1 and S1P regulate inflammation, and that inhibiting this pathway could inhibit inflammatory responses. To test this hypothesis we propose the following aims: 1) Establish that the SK1 and S1P pathway is regulated in inflammation and determine the mechanisms of this regulation. This will be done by determining if this pathway is regulated in inflammation and studying the mechanisms of this regulation in cell models of inflammation, and by determining the expression and cell-type distribution of SK1 in inflammatory tissues from humans and from animal models of inflammation. 2) Establish the function of SK1 and S1P in regulation of inflammation and determine the mechanisms of action of this pathway. This will be done by demonstrating that SK1 and S1P have a significant role in regulating inflammation by evaluating the effect of over expression of SK1 and of S1P treatment in cells and in vivo models of inflammation, and determining the mechanisms by which SK1 and S1P regulate inflammatory pathways (NF-KB, IL2, TNF, ERKs, COX-2). 3) Determine if SK1 and S1P are necessary for inflammation. This will be done by blocking SK1 activity in cells and in vivo using small interfering RNA to SK1 and/or dominant negative SK1. In addition we will test different compounds that we synthesized for their ability to inhibit SK1 or to antagonize S1P receptors in cells and in vivo models of inflammation. These studies will enable us to gain important insight into the role of this pathway in inflammatory responses and may also provide novel therapeutic approaches to inflammation.

描述（由申请人提供）：该项目的长期目标是定义由鞘氨醇1-磷酸盐（S1P）在炎症中介导的新型脂质途径的作用，并确定该途径的组成部分，作为抗炎治疗的潜在新靶标。 PI的实验室在鞘脂代谢和功能方面具有既定的专业知识记录。从上一个资金期开始的研究使我们朝着S1P在炎症中的作用和调节方面迈出了一个新颖的令人兴奋的方向。 S1P是通过鞘氨醇激酶（SK）在包括炎症细胞在内的许多细胞类型中通过磷酸化产生的。 S1P通过与G蛋白偶联受体S1P1-5的成员结合或细胞内的成员在细胞外作用。它介导了几种生物学活性，包括有丝分裂，细胞存活，血管生成和炎症反应。在这种竞争的更新中，我们有了引人注目的新数据，因此我们将这一途径牵涉到环氧合酶-2（COX-2）表达和前列腺素E2（PGE2）生产的关键调节剂。此外，我们发现SK1在炎症组织中显着过表达。我们还证明了细菌脂多糖（LPS）调节SK1。因此，该建议将检验以下假设：SK1和S1P调节炎症，并且抑制该途径可以抑制炎症反应。为了检验该假设，我们提出以下目的：1）确定SK1和S1P途径在炎症中受到调节，并确定该调节的机制。这将通过确定该途径是否在炎症中调节并研究这种调节的炎症细胞模型的机制，并确定人类炎症组织中SK1和炎症动物模型中SK1的表达和细胞类型分布。 2）确定SK1和S1P在调节炎症中的功能，并确定该途径的作用机理。这将通过证明SK1和S1P通过评估SK1和S1P处理过度表达在细胞和体内炎症模型中的过度表达和SK1和S1P调节炎症途径的机制（NF-KB，IL2，IL2，TNF，TNF，ERK，ERK，ERKS）来实现。 3）确定SK1和S1P是否需要炎症。这将通过使用小型干扰RNA对SK1和/或显性负SK1阻止细胞和体内的SK1活性来完成。此外，我们将测试我们合成的不同化合物，以抑制SK1或拮抗细胞中的S1P受体和体内炎症模型的能力。这些研究将使我们能够对该途径在炎症反应中的作用进行重要洞察力，还可以提供新颖的炎症治疗方法。