Molecular Determinants of Synaptic Plasticity in Chronic Pain

慢性疼痛突触可塑性的分子决定因素

基本信息

批准号：
10589545
负责人：
Shao-Rui Chen
金额：
$ 50.21万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589545
关键词：
Afferent Neurons Anions Behavioral Biochemical C-terminal Cations Cell Size Cell Volumes Clinical Data Development Down-Regulation Family member Gene Delivery Glutamate Receptor Glutamates Goals Hypersensitivity In Vitro Knowledge Leucine-Rich Repeat Link Mediating Molecular N-Methyl-D-Aspartate Receptors Neuronal Plasticity Neurons Neuropathy Nociception Paclitaxel Pain Phenotype Pilot Projects Play Posterior Horn Cells Proteins Regulation Role Sensory Signal Transduction Small Interfering RNA Spinal Spinal Cord Spinal Ganglia Synapses Synaptic plasticity Testing Therapeutic Transgenic Mice Traumatic Nerve Injury Vertebral column antagonist chemotherapy chemotherapy induced neuropathy chronic neuropathic pain chronic pain chronic pain management chronic painful condition conditional knockout dorsal horn in vivo innovation insight interdisciplinary approach knock-down nerve injury nervous system disorder novel novel therapeutics overexpression pain chronification pain model painful neuropathy presynaptic receptor coupling restraint trafficking transmission process

项目摘要

Molecular Determinants of Synaptic Plasticity in Chronic Pain The long-term goal of our project is to identify the molecular and signaling mechanisms that govern synaptic plasticity under chronic pain conditions. Neuropathic pain remains a major therapeutic challenge, and neuronal plasticity at the spinal cord level is fundamentally important to the development of chronic neuropathic pain. N- methyl-D-aspartate receptors (NMDARs) are expressed in primary sensory neurons and their central terminals in the spinal dorsal horn. However, they are functionally inactive under normal conditions and become tonically activated to potentiate glutamatergic input to spinal dorsal horn neurons after nerve injury and chemotherapy- induced neuropathy. The molecular mechanisms regulating the synaptic activity and trafficking of NMDARs in the spinal dorsal horn remain poorly understood. Volume-regulated anion channels, which are formed by multiple different leucine-rich repeat-containing protein 8 (LRRC8) family members, are crucial to the regulation of cell volume. In our pilot studies, we found that LRRC8A was highly expressed in dorsal root ganglion (DRG) neurons. Also, traumatic nerve injury selectively downregulated LRRC8A, but not LRRC8B-LRRC8D, in the DRG. Furthermore, LRRC8A downregulation or conditional knockout in DRG neurons induces NMDAR-dependent pain hypersensitivity. Importantly, we discovered that LRRC8A physically interacted with NMDARs to control synaptic trafficking and activity of NMDARs. In this renewal application, we will specifically determine the roles of LRRC8A in the regulation of nociception and synaptic NMDARs at the spinal cord level in two neuropathic pain models. On the basis of our intriguing preliminary data, we propose to test the overall hypothesis that LRRC8A protein directly interacts with NMDARs and normally restrains the synaptic trafficking of NMDARs at the spinal cord level; nerve injury or chemotherapy diminishes LRRC8A expression and augments the synaptic expression and activity of NMDARs, leading to increased glutamatergic input to spinal dorsal horn neurons and chronic pain. We will apply several innovative and complementary approaches, including biochemical and cellular analyses, transgenic mice, and synaptic recordings to study how LRRC8A controls NMDARs and nociception at molecular, cellular, and behavioral levels. Our project will generate fundamental new information about the molecular basis of NMDAR-mediated synaptic plasticity in neuropathic pain. Findings from our project are expected to advance our knowledge of molecular mechanisms of nociceptive regulation and to guide the development of new strategies for treating chronic neuropathic pain.

慢性疼痛突触可塑性的分子决定因素我们项目的长期目标是确定控制突触的分子和信号机制慢性疼痛条件下的可塑性。神经病理性疼痛仍然是一个主要的治疗挑战，神经元脊髓水平的可塑性对于慢性神经性疼痛的发展至关重要。 N- 甲基-D-天冬氨酸受体 (NMDAR) 在初级感觉神经元及其中枢末端表达在脊髓背角。然而，它们在正常情况下功能不活跃，并且变得强直神经损伤和化疗后激活以增强脊髓背角神经元的谷氨酸输入诱发神经病。调节 NMDAR 突触活性和运输的分子机制脊髓背角仍然知之甚少。容量调节的阴离子通道，由多个不同的富含亮氨酸重复序列的蛋白 8 (LRRC8) 家族成员，对于细胞的调节至关重要体积。在我们的初步研究中，我们发现 LRRC8A 在背根神经节 (DRG) 神经元中高表达。此外，创伤性神经损伤选择性下调 DRG 中的 LRRC8A，但不下调 LRRC8B-LRRC8D。此外，DRG 神经元中 LRRC8A 下调或条件性敲除可诱导 NMDAR 依赖性疼痛过敏。重要的是，我们发现 LRRC8A 与 NMDAR 发生物理相互作用来控制 NMDAR 的突触贩运和活动。在本次续签申请中，我们将具体确定角色 LRRC8A 在两种神经病患者脊髓水平的伤害感受和突触 NMDAR 调节中的作用疼痛模型。根据我们有趣的初步数据，我们建议检验以下总体假设： LRRC8A 蛋白直接与 NMDAR 相互作用，通常抑制 NMDAR 的突触运输脊髓水平；神经损伤或化疗会减少 LRRC8A 表达并增强突触 NMDAR 的表达和活性，导致脊髓背角神经元的谷氨酸输入增加慢性疼痛。我们将应用多种创新和互补的方法，包括生物化学和细胞分析、转基因小鼠和突触记录来研究 LRRC8A 如何控制 NMDAR 和分子、细胞和行为水平的伤害感受。我们的项目将产生基本的新信息关于 NMDAR 介导的神经性疼痛突触可塑性的分子基础。我们项目的调查结果预计将增进我们对伤害性调节分子机制的了解，并指导开发治疗慢性神经性疼痛的新策略。