MECHANISMS OF TRPV4-MEDIATED NEUROPATHIC PAIN

摘要 周围神经病是严重影响患者生活质量的最衰弱的疾病之一 造成反复出现的痛苦，并给我们的社会带来惊人的经济负担。神经性疼痛也代表着 一种严重的未得到满足的医疗需求，因为它对传统止痛药的反应往往很差，而且大多数 常用止痛药会产生严重的副作用。因此，重要的是识别细胞， 分子和神经回路在神经病理性疼痛发病的不同阶段中的特殊作用 以帮助开发基于机制的疗法。 瞬时受体电位(Trp)通道是一组作为细胞感受器表达的离子通道 通过多种细胞类型。TRPV4是一种多模式传感器，集成了各种热、机械和 化学刺激。根据初步研究，我们假设炎症反应需要TRPV4。 在脊髓中动态催化神经病理性疼痛。为了确定潜在的细胞机制 TRPV4介导的神经病理性疼痛我们将使用多学科方法结合细胞生成- 特异性TRPV4突变小鼠和骨髓嵌合体，表达TRPV4的细胞的光遗传激活 脊髓和神经病理性疼痛行为测试。我们还将确定药物抑制是否 TRPV4通道及表达TRPV4的脊髓细胞对周围神经的光发生抑制作用 损伤引起的神经病理性疼痛。 这一建议将为神经病理性疼痛期间依赖TRPV4的免疫激活奠定细胞基础。 并探索通过抑制TRPV4对神经炎症进行药理调节的可能性 功能。因此，这项研究为确定独特的分子和细胞靶点提供了一个独特的机会。 导致神经病理性疼痛的神经炎症性疾病的合理治疗设计。

SUMMARY Peripheral neuropathy is one of the most debilitating diseases that significantly impacts patient's quality of life with recurring pain and imposes staggering economic burdens to our society. Neuropathic pain also represents a critical unmet medical need because it tends to respond poorly to traditional analgesics and the most commonly used pain medicines produce serious side effects. Therefore, it is important to identify cells, molecules, and neural circuits specifically involved at different stages of the pathogenesis of neuropathic pain to help develop mechanism-based therapies. Transient receptor potential (TRP) channels are a group of ion channels serving as cellular sensors expressed by many cell types. TRPV4 is a polymodal sensory transducer integrating a variety of thermal, mechanical and chemical stimuli. Based on pilot studies, we hypothesize that TRPV4 is required for inflammatory responses that dynamically catalyze neuropathic pain in the spinal cord. To determine the cellular mechanisms underlying TRPV4-mediated neuropathic pain we will use a multidisciplinary approach combining generation of cell- specific TRPV4 mutant mice and bone marrow chimeras, optogenetic activation of TRPV4-expressing cells in the spinal cord, and neuropathic pain behavioral testing. We will also determine if pharmacological inhibition of TRPV4 channels and optogenetic inhibition of TRPV4-expressing spinal cells ameliorate peripheral nerve injury-induced neuropathic pain. This proposal will establish the cellular basis of TRPV4-dependent immune activation during neuropathic pain and explore the potential for pharmacological modulation of neuro-inflammation via inhibition of TRPV4 function. Thus, this study advances a unique opportunity to identify unique molecular and cellular targets for rational design of treatment for neuro-inflammatory diseases resulting in neuropathic pain.