Neurotrophic factors and excitability

神经营养因子和兴奋性

• 批准号: 7219383
• 负责人: GRANT D NICOL
• 金额: $ 23.72万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219383
• 关键词: Adult; Afferent Neurons; Agonist; Behavioral; Biological Models; Brain-Derived Neurotrophic Factor; Caliber; Capsaicin; Cells; Chronic; Condition; Dependence; Event; Exudate; Fire - disasters; Growth; Growth and Development function; Hyperalgesia; Inflammation; Inflammatory; Ion Channel; Laboratories; Lead; Measurement; Mechanics; Mediating; Mediation; Membrane; Modality; NGFR Protein; NGFR gene; Nerve Growth Factors; Neuroglia; Neurons; Neurotrophin 3; Nociception; Pathway interactions; Personal Satisfaction; Phosphotransferases; Play; Population; Potassium; Production; Property; Rattus; Regulation; Resistance; Role; Seminal; Signal Pathway; Sodium; Spinal Ganglia; Techniques; Tetrodotoxin; Time; Work; cell type; design; neuronal excitability; neurotrophic factor; neurotrophin 4; paracrine; patch clamp; receptor; response; transcriptional coactivator p75; voltage

DESCRIPTION (provided by applicant): Nerve growth factor (NGF) plays a critical role in the development and growth of sensory neurons. Seminal studies suggest that NGF may also play an important role in the regulating the sensitivity of sensory neurons to noxious stimulation. NGF levels are elevated in inflammatory exudates and is a potent causative agent in the production of both thermal and mechanical hyperalgesia. The behavioral findings suggest that the heightened sensitivity that occurs with inflammation may, in part, result from the actions of NGF on sensory neurons. There have been very few studies exploring the sensitizing actions of NGF on isolated neurons and their associated signaling pathways. Recent work in my laboratory demonstrates that NGF can rapidly augment the excitability of small diameter, capsaicin-sensitive sensory neurons through enhancement of the TTX-resistant sodium current and suppression of a voltage-dependent potassium current(s). Thus, NGF may have a significant impact on the state of neuronal excitability. The notion that NGF may be an important paracrine-type messenger in mediating the excitability of sensory neurons on a rapid time scale, perhaps less than one minute, is a completely unexplored idea. The Specific Aims outlined in this proposal are: Aim 1 will determine the effects of NGF on the excitability as well as the modulation of a variety of membrane currents that are critical in setting the firing level of the neuron. These studies will establish whether this sensitization results from activation of Trk A and/or p75 NTR. Aim 2 will follow an identical course of study to determine whether the other neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3) rapidly modulate the excitability and selected membrane currents. These studies will examine the role of Trk B, Trk C, and/or p75 receptors in modulating excitability. Aim 3 will establish whether glial cell-derived neurotrophic factor (GDNF) can rapidly modulate selected membrane currents in sensory neurons. GDNF plays a critical role in the growth and survival of a distinct population of non-peptidergic sensory neurons that lose their dependence on NGF. Aim 4 will explore the intracellular signaling pathways that mediate the rapid modulatory effects of NGF acting through Trk A and p75 NTRs, BDNF and NT-4 through Trk B, NT-3 through Trk C, and GDNF through the Ret kinase pathway. These studies will further our understanding of the cellular mechanisms and signaling pathways whereby neurotrophins acutely regulate the excitability of both nociceptive and non-nociceptive sensory neurons. A fundamental understanding of such events could lead to better designed compounds and therapies to facilitate the treatment of chronic inflammatory conditions.

描述（由申请人提供）：神经生长因子（NGF）在感觉神经元的发育和生长中起关键作用。研究提示，NGF在调节感觉神经元对伤害性刺激的敏感性中也起重要作用。NGF水平在炎性渗出物中升高，并且是热痛觉过敏和机械痛觉过敏两者的产生中的有效致病剂。行为研究结果表明，炎症引起的敏感性升高可能部分是由于NGF对感觉神经元的作用。关于NGF对离体神经元的致敏作用及其相关信号通路的研究很少。在我的实验室最近的工作表明，神经生长因子可以迅速增加小直径，辣椒素敏感的感觉神经元的兴奋性，通过增强TTX抗性钠电流和抑制电压依赖性钾电流（S）。因此，NGF可能对神经元兴奋性的状态具有显著影响。NGF可能是一种重要的旁分泌型信使，在快速的时间尺度上（可能不到一分钟）介导感觉神经元的兴奋性，这是一个完全未探索的想法。本提案中概述的具体目标是：目标1将确定NGF对兴奋性的影响以及对各种膜电流的调制，这些膜电流在设定神经元的放电水平方面至关重要。这些研究将确定这种致敏是否由Trk A和/或p75 NTR的激活引起。目的2将遵循相同的研究过程，以确定其他神经营养因子脑源性神经营养因子（BDNF），神经营养因子-4（NT-4）和神经营养因子-3（NT-3）是否快速调节兴奋性和选定的膜电流。这些研究将检查Trk B、Trk C和/或p75受体在调节兴奋性中的作用。目的3建立胶质细胞源性神经营养因子（GDNF）是否能快速调节感觉神经元的膜电流。GDNF在失去对NGF依赖性的非肽能感觉神经元的生长和存活中起关键作用。目的4探讨NGF通过Trk A和p75 NTRs、BDNF和NT-4通过Trk B、NT-3通过Trk C、GDNF通过Ret激酶途径介导快速调节效应的细胞内信号通路。这些研究将进一步加深我们对神经营养因子急性调节伤害性和非伤害性感觉神经元兴奋性的细胞机制和信号通路的理解。对这些事件的基本理解可能会导致更好地设计化合物和治疗方法，以促进慢性炎症疾病的治疗。