Sphingosine 1-Phosphate Receptors and Sensitization of Sensory Neurons

1-磷酸鞘氨醇受体和感觉神经元的敏化

基本信息

批准号：
7895928
负责人：
GRANT D NICOL
金额：
$ 52.94万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2009-07-17 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895928
关键词：
Action Potentials Affect Afferent Neurons Animals Behavior Behavioral Binding Biochemical Pathway Biological Models Blood Platelets Caliber Capsaicin Cardiac Cells Chemotaxis Collaborations Communication Dinoprostone Environment Event Exposure to Family G-Protein-Coupled Receptors GTP-Binding Proteins Genes Goals Grant Immune Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intervention Ion Channel Knowledge Lead Learning Ligands Lysophospholipids Maintenance Mediating Membrane Messenger RNA Molecular Names Nerve Growth Factors Neurons Nociception Pain Pathway interactions Perception Perfusion Physiological Play Population Potassium Principal Investigator Rattus Regulation Resistance Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Small Interfering RNA Sodium Sphingosine-1-Phosphate Receptor Stimulus System TRPV1 gene Tetrodotoxin Therapeutic Intervention United States National Institutes of Health Work afferent nerve in vivo knock-down mast cell member migration nerve injury neuronal excitability novel patch clamp receptor research study response sphingosine 1-phosphate tool

项目摘要

Inflammation can augment dramatically the sensitivity of nociceptive sensory neurons. In some cases, the actions of inflammatory mediators are fairly well understood; however, there are signalling pathways for which we have very little knowledge. Such a pathway is the one in which the activating ligand is sphingosine 1- phosphate (S1P). Upon activation, S1P is released from a variety of immuno-competent cells and appears to play an important role in their chemotaxis and migration. S1 P is the endogenous ligand for a family of G protein-coupled receptors originally named EDG receptors (endothelial differentiation gene) and are now known as the S1 P receptor family (S1 PRJ. Our understanding of the role of S1 P in the onset and regulation of the inflammatory response is very limited, even in model systems. In our work on NGF, we discovered that externally applied S1 P significantly increased neuronal excitability and that these neurons expressed the mRNA for S1 PRs. Because of the emerging importance of S1 P in the onset of inflammation, this raises the question whether S1 P is an important primary messenger communicating between inflammatory cells and sensory neurons. To answer this question, three SAs are proposed: SA1 will establish which S1 PRs are expressed in sensory neurons and whether these receptors co-localize with specific defined populations of sensory neurons. SA2 will determine, using patch-clamp recording, which specific membrane currents are modulated by S1 P and how these changes lead to enhanced neuronal firing. S1 PRs involved in this sensitization will be determined by single-cell RT-PCR analysis and siRNA to knock-down the expression of specific receptors. SA3 in collaboration with Dr. Jun-Ming Zhang, will determine the capacity of S1 P to affect nociceptive behaviors in rats wherein S1 P is perfused directly onto the L5 DRG. Results from such studies will provide an important understanding of the potential communication between the immune and neuronal systems and lead to interventions that reduce the enhanced pain associated with inflammation.

炎症可以显着增强伤害感受感觉神经元的敏感性。在某些情况下，炎症介体的行为已经相当理解了。但是，有一些信号通路我们知识很少。这样的途径是激活配体是1-磷酸盐（S1P）的途径。激活后，S1P从多种免疫能力的细胞中释放出来，似乎在其趋化性和迁移中起着重要作用。 S1 P是用于G蛋白耦合受体家族的内源配体，称为EDG受体（内皮分化基因），现在被称为S1 P受体家族（S1 PRJ。我们对S1 P在炎症响应中的发作和调节中的作用的理解非常有限，甚至在模型系统中都非常有限。兴奋性和这些神经元在炎症的发作中表达了S1 PR的mRNA。感觉神经元将使用贴片钳记录确定哪些特定的膜电流由S1 P调节，以及这些变化如何导致神经元的增强。参与此敏化的S1 PR将通过单细胞RT-PCR分析和siRNA来确定，以敲低特定受体的表达。 SA3与Jun-Ming Zhang博士合作，将确定S1 P影响大鼠伤害性行为的能力，其中S1 P直接灌注到L5 DRG上。此类研究的结果将为免疫系统和神经元系统之间的潜在通信提供重要的理解，并导致干预措施减轻与炎症相关的疼痛。