Lipase Products Mediate Sensitization of Sensory Neurons

脂肪酶产品介导感觉神经元的敏化

• 批准号: 7156917
• 负责人: MICHAEL R VASKO
• 金额: $ 33.22万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156917
• 关键词: 1,2-diacylglycerol; Accounting; Acids; Acute; Adult; Afferent Neurons; Agonist; Anabolism; Animals; Arachidonic Acids; Bradykinin; Calcitonin Gene-Related Peptide; Caliber; Cells; Chronic; Communication; Coupled; Cyclic AMP; Diacylglycerol Kinase; Diglycerides; Disease; Dorsal; Drug usage; Edg-7 Receptor; Eicosanoids; Enzymes; Esthesia; Experimental Models; Extravasation; GTP-Binding Proteins; Gene Family; Hyperalgesia; Hypersensitivity; Infection; Inflammation; Inflammatory; Inositol; Isoenzymes; Knowledge; Laboratories; Lipase; Lysophospholipids; Mediating; Mediator of activation protein; Metabolic; Metabotropic Glutamate Receptors; Mitogen-Activated Protein Kinases; Modeling; Neuraxis; Neurogenic Inflammation; Neurons; Neuropeptides; Nociception; Numbers; Pain; Pathway interactions; Peptides; Perception; Peripheral; Pharmacotherapy; Phosphatidate Phosphatase; Phosphatidic Acid; Phospholipase; Phospholipase A2; Phospholipase C; Physiological; Physiological Processes; Plasma; Process; Production; Prostaglandins; Protein Kinase C; Proteins; Rat-1; Rate; Rattus; Receptor Protein-Tyrosine Kinases; Role; Second Messenger Systems; Sensory; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Slice; Sphingosine; Sphingosine-1-Phosphate Receptor; Spinal Cord; Spinal Ganglia; Stimulus; Substance P; Tissues; Vasodilation; Vasodilation disorder; Work; cell type; design; indexing; inorganic phosphate; lysophosphatidic acid; neuronal excitability; novel; receptor; second messenger

DESCRIPTION (provided by applicant): Lipases are critically important in signal transduction in that they produce a number of first and second messengers that mediate numerous physiological processes. These lipases include phospholipase A2s which liberate arachidonic acid (the rate limiting step in eicosanoid biosynthesis), phospholipase Cs which liberate inositol trisphosphate and diacylglycerols (DAGs), and phospholipase Ds which synthesize phosphatidic acids (PAs) and lysophosphatidic acids (LPAs). Although much work has focused on the involvement of products of PLA2s in pain and inflammation, few studies have examined whether other lipase products modulate neurogenic inflammation and nociception. A major mechanism to account for both neurogenic inflammation and enhanced pain sensitization involves augmenting the activity of small diameter sensory neurons with the subsequent release of neuropeptides from these neurons. Consequently, the studies outlined in this proposal will examine the effects of various lipase products on sensitization of sensory neurons. We also will determine whether select inflammatory mediators augment peptide release from sensory neurons and whether these actions are mediated by lipase products. Studies also will determine whether peripheral inflammation increases the activity of the PLC and PLD signaling pathways and thus contributes to long-term sensitization. The role of lipase products will be studied using two experimental models: (1) rat sensory neurons grown in culture, and (2) spinal cord and dorsal root ganglia (DRGs) from rats with unilateral inflammation. The former model provides a unique opportunity to examine the mechanisms of action of lipase products on sensory neurons and the transduction cascades activated by inflammatory mediators without significant interference from other types of cells. The latter model affords the opportunity to study actions of lipases at the level of sensory input to the central nervous system in naive animals or during chronic inflammation. We will manipulate the lipase transduction cascades by using drugs that inhibit specific enzymes in the pathways, by reducing expression of specific proteins with small linterfering RNA, and by over expressing proteins by infection with adenoviral constructs. The ability of lipase products to augment stimulated release of the neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP) from sensory neurons and to increase excitability will be used as indices of sensitization. These studies will provide basic information as to the transduction cascades that mediate neuronal sensitivity during inflammation. This knowledge is critically important for understanding the process of neurogenic inflammation and in ultimately designing new drug therapies for the management of inflammatory diseases.

描述（由申请人提供）：脂肪酶在信号转导中至关重要，因为它们产生许多介导许多生理过程的第一和第二信使。这些脂肪酶包括释放花生四烯酸（类二十烷酸生物合成中的限速步骤）的磷脂酶 A2、释放三磷酸肌醇和二酰基甘油 (DAG) 的磷脂酶 Cs，以及合成磷脂酸 (PA) 和溶血磷脂酸 (LPA) 的磷脂酶 D。尽管很多工作都集中在 PLA2 产物与疼痛和炎症的关系上，但很少有研究探讨其他脂肪酶产物是否调节神经源性炎症和伤害感受。解释神经源性炎症和增强的疼痛敏化的主要机制涉及增强小直径感觉神经元的活性以及随后从这些神经元释放神经肽。因此，本提案中概述的研究将检查各种脂肪酶产品对感觉神经元敏化的影响。我们还将确定特定的炎症介质是否会增加感觉神经元的肽释放，以及这些作用是否是由脂肪酶产物介导的。研究还将确定外周炎症是否会增加 PLC 和 PLD 信号通路的活性，从而有助于长期致敏。 将使用两种实验模型来研究脂肪酶产品的作用：(1) 培养物中生长的大鼠感觉神经元，以及 (2) 来自单侧炎症大鼠的脊髓和背根神经节 (DRG)。前一种模型提供了一个独特的机会来检查脂肪酶产品对感觉神经元的作用机制以及炎症介质激活的转导级联，而不受其他类型细胞的显着干扰。后一种模型提供了研究在幼稚动物或慢性炎症期间中枢神经系统感觉输入水平上脂肪酶的作用的机会。我们将通过使用抑制途径中特定酶的药物、通过小干扰RNA减少特定蛋白质的表达以及通过用腺病毒构建体感染来过度表达蛋白质来操纵脂肪酶转导级联。脂肪酶产品增强感觉神经元刺激释放神经肽、P 物质 (SP) 和降钙素基因相关肽 (CGRP) 并增加兴奋性的能力将被用作敏化指标。这些研究将提供有关炎症期间介导神经元敏感性的转导级联的基本信息。这些知识对于理解神经源性炎症的过程以及最终设计治疗炎症性疾病的新药物疗法至关重要。