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：
7653304
负责人：
GRANT D NICOL
金额：
$ 53.08万
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7653304
关键词：
Action Potentials Acute Address Adrenal Cortex Hormones Affect Afferent Neurons Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Aspirate substance Axotomy Behavior Behavioral Binding Biochemical Pathway Biological Models Biology Blood Platelets Caliber Capsaicin Cardiac Cell Culture Techniques Cells Characteristics Chemicals Chemotaxis Chronic Collaborations Communication Data Deposition Detection Development Dinoprostone Dose Drops Effectiveness Environment Event Exposure to Family Fire - disasters Freezing Frequencies G-Protein-Coupled Receptors GDNF gene GTP-Binding Proteins Generations Genes Goals Heating Housekeeping Gene Hypersensitivity Hypoxanthines Immune Implant In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injection of therapeutic agent Intention Intervention Ion Channel Knockout Mice Knowledge Laboratories Lead Learning Left Ligands Ligation Lung Maintenance Measurement Measures Mechanics Mediating Membrane Messenger RNA Methods Microelectrodes Modeling Molecular Names Nerve Growth Factors Neurons Neuropeptides Nociception Operative Surgical Procedures Outcome Pain Paper Pathologic Pathway interactions Perception Perfusion Peripheral Peripheral Nerves Phenotype Physiological Play Population Potassium Preparation Property Proteins Protocols documentation Publishing Pump Ramp Rattus Reaction Reaction Time Recovery Regulation Research Design Research Institute Resistance Reverse Transcriptase Polymerase Chain Reaction Role Running Sampling Signal Pathway Signal Transduction Site Small Interfering RNA Sodium Sphingosine Sphingosine-1-Phosphate Receptor Spinal nerve structure Spleen Staging Staining method Stains Stimulus Substance P System TRPV1 gene Testing Tetrodotoxin Therapeutic Intervention Thermal Hyperalgesias Time Tissues Transferase Tube Universities Western Blotting Whole-Cell Recordings Work Zymosan afferent nerve base behavior measurement carbene cell type cytokine human WFDC2 protein implantation improved in vivo indium arsenide inhibitor/antagonist kinase inhibitor knock-down mast cell mechanical allodynia member migration nerve injury neuronal cell body neuronal excitability nociceptive response novel pain behavior patch clamp receptor research study response sphingosine 1-phosphate sphingosine kinase spinal nerve posterior root voltage voltage clamp

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性感觉神经元的敏感性。在某些情况下，人们对炎症介质的作用已相当了解。然而，我们对某些信号通路知之甚少。在这样的途径中，激活配体是1-磷酸鞘氨醇(S1P)。激活后，S1P 从多种免疫活性细胞中释放出来，似乎在它们的趋化性和迁移中发挥重要作用。 S1 P 是 G 蛋白偶联受体家族的内源配体，最初称为 EDG 受体（内皮分化基因），现在称为 S1 P 受体家族（S1 PRJ）。我们对 S1 P 在发病和发生中的作用的理解即使在模型系统中，炎症反应的调节也非常有限。在我们对 NGF 的研究中，我们发现外部应用 S1 P 显着增加神经元兴奋性，并且这些神经元表达 S1 的 mRNA。由于 S1 P 在炎症发生中的重要性日益凸显，这就提出了一个问题：S1 P 是否是炎症细胞和感觉神经元之间沟通的重要主要信使。为了回答这个问题，提出了三个 SA：SA1 将确定哪一个。 S1 PR 在感觉神经元中表达，这些受体是否与特定定义的感觉神经元群共定位，SA2 将使用膜片钳记录确定哪些特定膜电流受 S1 P 调节以及这些变化如何。导致神经元放电增强。参与这种致敏作用的 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 与张俊明博士合作，将确定 S1 P 影响大鼠伤害感受行为的能力，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系统之间的潜在沟通提供重要的了解，并导致减少与炎症相关的增强疼痛的干预措施。