Molecular and cellular functions of Trk receptors in axonal induction and resolution of nociceptor excitability

Trk 受体在轴突诱导和伤害感受器兴奋性解决中的分子和细胞功能

• 批准号: 451491097
• 负责人: Dr. Michael Briese
• 金额: --
• 依托单位: Institut für Klinische Neurobiologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/451491097?language=en
• 关键词: Molecular; cellular; functions; Trk; receptors

Signaling mechanisms for enhanced transduction of nociceptive stimuli are key to understanding the cellular basis of pain persistence and resolution. Nerve growth factor (NGF) and other members of the neurotrophin family are well-known for their role in promoting neuronal survival and modulating function of nociceptors and other types of sensory neurons. NGF can induce long-lasting pain through upregulation of brain-derived-neurotrophic factor (BDNF) expression that acts both on postsynaptic neurons in the spinal cord as well as in an auto-paracrine manner on presynaptic TrkB receptors on nociceptive neurons. The mechanisms that then lead to pain persistence or resolution are not fully understood, but multiple lines of evidence suggest that altered gene expression, altered subcellular transport of specific mRNAs, and altered translational control in axons of nociceptors contribute to chronic pain. In this project, we would like to follow the hypothesis that neurotrophins potentiate axonal translocation of specific mRNAs and also regulate the local presynaptic translation of these transcripts for the induction of long-term changes at presynaptic sites that lead to enhanced excitability and synaptic activity of nociceptive sensory neurons and thus to pain chronification. Pain resolution depends on the reversion of these mechanisms. Using compartmentalized cultures of nociceptive sensory neurons, we would like to investigate changes in the axonal transcriptomes of nociceptors that occur when axons are locally exposed to NGF, and identify alterations both in general transcript levels and, in particular, in transcripts for which the translocation to axonal compartments is specifically enhanced. We also hypothesize that elevated TrkB and BDNF expression and release of this neurotrophic factor from presynaptic terminals of nociceptors induces autocrine presynaptic activation of TrkB, which then induces longterm changes in local protein synthesis in chronic pain. These results could be a basis for development of new strategies for pain resolution, based on strategies that abolish TrkB responsiveness at these synaptic sites.

增强伤害性刺激转导的信号机制是理解疼痛持续和解决的细胞基础的关键。神经生长因子（NGF）和神经营养因子家族的其他成员因其促进神经元存活和调节伤害感受器和其他类型感觉神经元的功能而闻名。NGF可以通过上调脑源性神经营养因子（BDNF）的表达来诱导持久疼痛，BDNF既作用于脊髓突触后神经元，也以自身旁分泌的方式作用于伤害性神经元的突触前TrkB受体。导致疼痛持续或消退的机制尚不完全清楚，但多种证据表明，基因表达的改变，特定mrna的亚细胞运输的改变，以及伤害感受器轴突翻译控制的改变有助于慢性疼痛。在这个项目中，我们希望遵循神经营养因子增强特定mrna轴突易位的假设，并调节这些转录本的局部突触前翻译，以诱导突触前位点的长期变化，从而增强伤害感觉神经元的兴奋性和突触活性，从而导致疼痛的慢性化。疼痛的解决取决于这些机制的恢复。利用区室化的伤害感觉神经元培养，我们希望研究当轴突局部暴露于NGF时，伤害感受器轴突转录组的变化，并确定一般转录水平的变化，特别是轴突区室易位特异性增强的转录物的变化。我们还假设，TrkB和BDNF的表达升高，以及这种神经营养因子从伤害感受器的突触前末端释放，诱导TrkB的突触前自分泌激活，进而诱导慢性疼痛局部蛋白质合成的长期变化。这些结果可能是开发疼痛解决新策略的基础，该策略基于消除这些突触部位的TrkB反应性的策略。