NEURON-GLIA INTERACTIONS IN TRIGEMINAL GANGLIA AS A BASIS FOR FUTURE THERAPY

三叉神经节中神经元-胶质细胞的相互作用作为未来治疗的基础

• 批准号: 7258444
• 负责人: LI-YEN M HUANG
• 金额: $ 35.36万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258444
• 关键词: Acids; Afferent Neurons; Agonist; Behavior; Behavioral; Biological Assay; Bioluminescence; Cell Communication; Cells; Chronic; Chronic intense pain; Citric Acid Cycle; Communication; Complex; Condition; Development; Disease; Dyes; Electric Stimulation; Endocytosis; Enzyme-Linked Immunosorbent Assay; Enzymes; Exocytosis; Face; Feedback; Fire - disasters; Freund' s Adjuvant; Future; Ganglia; Genetic; Goals; Image Analysis; Immunosorbents; In Vitro; Inflammation; Inflammatory; Injury; Ion Channel; Jaw; Knowledge; Link; Maintenance; Measures; Mediating; Membrane; Methods; Monitor; Myxoid cyst; Nerve; Nerve Fibers; Neuraxis; Neuroglia; Neurons; Neuropathy; Nociception; Nucleotides; Orofacial Pain; P2X-receptor; Pain; Pain Disorder; Patients; Pattern; Peripheral; Peripheral Nerves; Personal Satisfaction; Plant Roots; Play; Production; Public Health; Purinoceptor; Rattus; Recombinants; Research; Research Personnel; Role; Sensory; Signal Transduction; Skin; Small Interfering RNA; Spinal Cord; Spinal Ganglia; Structure; Structure of trigeminal ganglion; TRPV1 gene; Testing; Tetanus Toxin; Therapeutic; Time; Tooth structure; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Vanilloid; Viral; Viscera; autocrine; base; chronic pain; cytokine; design; ganglion cell; human TNF protein; immunocytochemistry; in vivo; insight; knock-down; nerve injury; neuronal cell body; neuronal excitability; nociceptive response; orofacial; paracrine; programs; receptor; receptor expression; repaired; response; satellite cell; transmission process; vector

DESCRIPTION (provided by applicant): Recent studies of cytokine actions in the spinal cord and dorsal root ganglia suggest that neuron-glia interactions are important in initiating and maintaining chronic pain states. How this is accomplished remains unclear. Disorders of the orofacial complex often produce intense chronic pain in patients and results in devastating consequences in their well being. The long-term goal of this research is to understand neuron-glia interactions in the trigeminal ganglion (TG), the primary afferent structure for the orofacial region. Our focus will be to understand the critical role that transmitters released from neuronal somata (cell bodies) of TGs play in neuron- satellite glial cell communication. We hypothesize that excessive firing in TG neurons elicits somatic release of ATP from neuronal somata. ATP activates satellite cells and evokes cytokine release from these cells. Cytokines in turn sensitize the neuronal somata and further increase their activity. In vitro and in vivo approaches will be used to test this hypothesis of positive feedback loop. We will (1) identify the transmitters released from neuronal somata of TGs (2) examine the communication between neuron and satellite cells (3) determine the effects of cytokines on P2X and TRPV receptor-mediated responses, (4) examine the action of cytokines on nociceptive responses in rats and determine the possibility of using siRNA to down-regulate receptors involved in neuron-glia communication and thus to relieve orofacial nociception. Normal, inflamed and nerve-ligated rats will be used. Transmitter release and membrane currents will be measured with patch pipettes; intracellular Ca2+ concentrations will be monitored with Ca2+ dyes; expression of P2X and TRPV receptors will be examined with immunocytochemistry and Western analyses. These studies should provide a better understanding of the mechanisms underlying neuron-glia interactions in TGs. The knowledge will be critical for designing better therapies for the treatment of orofacial pain.

描述（由申请人提供）：最近对脊髓和背根神经节中细胞因子作用的研究表明，神经元-胶质细胞相互作用在启动和维持慢性疼痛状态中很重要。这是如何实现的尚不清楚。口腔面部复合体的紊乱常常给患者带来强烈的慢性疼痛，并对他们的健康造成毁灭性的后果。本研究的长期目标是了解三叉神经节（TG）中神经元-胶质细胞的相互作用，三叉神经节是口面区的主要传入结构。我们的重点将是了解从TGs的神经元体（细胞体）释放的递质在神经元-卫星胶质细胞通讯中所起的关键作用。我们假设TG神经元的过度放电引发了神经元体细胞释放ATP。ATP激活卫星细胞并促使细胞因子从这些细胞中释放出来。细胞因子反过来使神经元体敏感并进一步增加其活性。在体外和体内的方法将被用来测试这一假设的正反馈回路。我们将(1)鉴定TGs神经元体释放的递质(2)检查神经元和卫星细胞之间的通讯(3)确定细胞因子对P2X和TRPV受体介导的反应的影响，(4)检查细胞因子对大鼠伤害反应的作用，并确定利用siRNA下调参与神经元-胶质细胞通讯的受体从而减轻口面部伤害感觉的可能性。正常，发炎和神经结扎的大鼠将被使用。递质释放和膜电流将用膜片移液器测量；用Ca2+染料监测细胞内Ca2+浓度；P2X和TRPV受体的表达将通过免疫细胞化学和Western分析进行检测。这些研究将有助于更好地理解tg中神经元-胶质细胞相互作用的机制。这些知识对于设计更好的治疗口面部疼痛的疗法至关重要。