MECHANISMS OF TRPV4-MEDIATED NEUROPATHIC PAIN

TRPV4 介导的神经病理性疼痛的机制

基本信息

批准号：
10204872
负责人：
Hongzhen Hu
金额：
$ 50.53万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204872
关键词：
Ablation Acute Acute Pain Affect Afferent Neurons Analgesics Anticonvulsants Antidepressive Agents Attenuated Behavior Blood Bone Marrow CCL2 gene Cations Cells Chemicals Chimera organism Clinic Complement Disease Economic Burden Endothelial Cells Generations Genetic Immune Inflammation Mediators Inflammatory Inflammatory Response Injury Ion Channel Lead Ligands Maintenance Mechanics Mediating Medical Medicine Microglia Modeling Molecular Molecular Target Mutant Strains Mice Nerve Pain Neuroimmune Neurons Neuropathy Nociception Nociceptors Opioid Pain Pathogenesis Pathologic Processes Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Peripheral nerve injury Permeability Persistent pain Pharmacology Pharmacology Study Phase Physiological Processes Pilot Projects Play Population Prevention Production Productivity Protein Kinase M Quality of life Reagent Reporting Resistance Rest Role Sensory Sensory Process Signal Transduction Societies Spinal Spinal Cord Spinal Ganglia Stimulus TRP channel Testing Therapeutic Tissues Transducers Up-Regulation Vascular Endothelial Cell base behavior test cell type cellular targeting chemokine chemotherapy induced neuropathy chronic neuropathic pain chronic pain cytokine effective therapy experimental study first responder immune activation improved in vivo interdisciplinary approach macrophage member monocyte mouse model nerve injury neural circuit neuroinflammation new therapeutic target novel therapeutic intervention optogenetics p38 Mitogen Activated Protein Kinase painful neuropathy receptor recombinase-mediated cassette exchange response sensor side effect spared nerve therapy design tool

项目摘要

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.

概括周围神经病是最令人衰弱的疾病之一，可显着影响患者的生活质量反复出现的痛苦并给我们的社会施加了惊人的经济负担。神经性疼痛也代表关键的未满足医疗需求，因为它对传统镇痛药的反应较差常用的止痛药会产生严重的副作用。因此，识别细胞很重要，分子和神经回路特别涉及神经性疼痛发病机理的不同阶段帮助开发基于机制的疗法。瞬态受体电位（TRP）通道是一组作为表达的细胞传感器的离子通道通过许多细胞类型。 TRPV4是一种多聚词传感器，整合了各种热，机械和化学刺激。基于试点研究，我们假设TRPV4是炎症反应所必需的这种动态催化脊髓的神经性疼痛。确定基础的细胞机制 TRPV4介导的神经性疼痛我们将使用一种多学科方法，结合了细胞的产生特定的TRPV4突变小鼠和骨髓嵌合体，表达TRPV4细胞的光遗传激活脊髓和神经性疼痛行为测试。我们还将确定药理学抑制是否 TRPV4通道和表达TRPV4表达脊柱细胞的光学抑制作用改善周围神经受伤引起的神经性疼痛。该建议将在神经性疼痛期间建立TRPV4依赖性免疫激活的细胞基础并探索通过抑制TRPV4的药理调节神经炎症的潜力功能。因此，这项研究为确定独特的分子和细胞靶标而促进了独特的机会神经炎症性疾病的治疗的合理设计导致神经性疼痛。