MECHANISMS OF TRPV4-MEDIATED NEUROPATHIC PAIN

总结 周围神经病变是一种严重影响患者生活质量的疾病 它给我们的社会带来了惊人的经济负担。神经性疼痛也代表了 这是一个关键的未满足的医疗需求，因为它往往对传统镇痛药反应不佳， 常用的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，特别是在神经病理性疼痛的发病机制的不同阶段 来帮助开发基于机制的疗法。 瞬时受体电位（TRP）通道是一类作为细胞传感器表达的离子通道， 许多细胞类型。TRPV 4是一种多模态传感器，集成了各种热、机械和 化学刺激基于初步研究，我们假设TRPV4是炎症反应所必需的， 在脊髓中动态催化神经性疼痛。为了确定潜在的细胞机制 TRPV4介导的神经病理性疼痛，我们将使用多学科的方法结合细胞的产生， 特异性TRPV4突变小鼠和骨髓嵌合体中TRPV4表达细胞的光遗传学活化， 脊髓和神经性疼痛行为测试。我们还将确定药物抑制 TRPV4通道和TRPV4表达脊髓细胞的光遗传学抑制改善周围神经 损伤引起的神经性疼痛。 该提案将建立神经性疼痛期间TRPV 4依赖性免疫激活的细胞基础 并探索通过抑制TRPV4来药理学调节神经炎症的潜力 功能因此，这项研究提出了一个独特的机会，以确定独特的分子和细胞靶点， 合理设计导致神经性疼痛的神经炎性疾病的治疗。

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.