Neurotrophic factors and excitability

神经营养因子和兴奋性

• 批准号: 6700312
• 负责人: GRANT D NICOL
• 金额: $ 25.02万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700312
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; brain derived neurotrophic factor; electrical potential; gene targeting; genetically modified animals; glia; immunocytochemistry; inflammation; laboratory mouse; laboratory rat; membrane potentials; nerve growth factors; neurogenesis; neurons; polymerase chain reaction; tissue /cell culture; voltage /patch clamp; western blottings

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）在感觉神经元的发展和生长中起关键作用。开创性研究表明，NGF在调节感觉神经元对有害刺激的敏感性方面也可能起重要作用。 NGF水平在炎症性渗出液中升高，并且是热和机械痛觉过敏的产生的有效病因。行为发现表明，炎症发生的敏感性提高可能部分是由于NGF对感觉神经元的作用而引起的。很少有研究探索NGF对孤立神经元及其相关信号通路的敏感性作用。我的实验室中最近的工作表明，NGF可以通过增强TTX耐钠电流和电压依赖性钾电流（S）来快速提高小直径，辣椒素敏感的感觉神经元的兴奋性。因此，NGF可能会对神经元兴奋性状态产生重大影响。 NGF在快速时间尺度上介导感觉神经元的兴奋性（可能不到一分钟的时间）时，NGF可能是一个重要的旁分泌型信使，这是一个完全没有探索的想法。该提案中概述的具体目的是：AIM 1将确定NGF对兴奋性的影响以及对设定神经元点火水平至关重要的各种膜电流的调节。这些研究将确定这种敏化是否是由TRK A和/或P75 NTR的激活引起的。 AIM 2将遵循相同的研究过程，以确定其他神经营养蛋白脑源性神经营养因子（BDNF），Neurotrophin-4（NT-4）（NT-4）和Neurotrophin-3（NT-3）是否会迅速调节兴奋性和选定的膜流液。 。这些研究将研究TRK B，TRK C和/或p75受体在调节兴奋性中的作用。 AIM 3将确定神经胶质细胞衍生的神经营养因子（GDNF）是否可以快速调节感觉神经元中选定的膜电流。 GDNF在不同依赖NGF的非肽性感觉神经元的不同种群的生长和生存中起着至关重要的作用。 AIM 4将探索通过TRK A和P75 NTR，BDNF和NT-4通过TRK B，NT-3，NT-3，NT-3，NT-3通过TRK C和GDNF通过RET Kinase途径的NGF的快速调节效应的细胞内信号通路。这些研究将进一步了解细胞机制和信号通路，神经营养蛋白急性调节伤害感受和非伤害感受感官神经元的兴奋性。对此类事件的基本理解可能会导致更好地设计的化合物和疗法，以促进慢性炎症状况的治疗。