Validation of blocking TSP4/Cava2d1 interaction as a new target for neuropathic pain

验证阻断 TSP4/Cava2d1 相互作用作为神经性疼痛的新靶点

• 批准号: 10670457
• 负责人: ZHIGANG David LUO
• 金额: $ 9.66万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-24 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670457
• 关键词: Action Potentials; Afferent Neurons; Affinity; Analgesics; Animal Model; Animals; Binding; Biological Assay; Calcium Channel; Clinical Research; Coculture Techniques; Collaborations; Development; Dorsal; Dose; EGF gene; EGF-Like Domain; Excitatory Synapse; Extracellular Matrix Proteins; Frequencies; Future; Generations; Genes; Genetic; Goals; Helping to End Addiction Long-term; In Vitro; Injury; Laboratories; Lead; Ligation; Measures; Mediating; Medical; Medication Management; Modeling; National Center for Advancing Translational Sciences; Neurons; Neuropathy; Pain; Pain management; Pathologic; Pathway interactions; Peptides; Peripheral nerve injury; Pharmaceutical Preparations; Phase; Play; Posterior Horn Cells; Protein Subunits; Proteins; Rattus; Research Personnel; Role; Self Administration; Sensory; Side; Site; Slice; Spinal; Spinal Anesthesia; Spinal Cord; Spinal Ganglia; Spinal nerve structure; Structure of trigeminal ganglion; Synapses; Synaptic Transmission; Testing; Therapeutic; Therapeutic Agents; Thermal Hyperalgesias; Time; Trigeminal nerve structure; United States National Institutes of Health; Up-Regulation; Validation; abuse liability; allodynia; behavior test; blind; chronic pain management; experimental study; interdisciplinary approach; nerve injury; neurotransmission; novel; pain model; pain signal; painful neuropathy; preference; prevent; response; spontaneous pain; synaptogenesis; therapeutic target; therapy development; thrombospondin 4; voltage

Project Summary/Abstract Validation of a novel pain target is a critical step toward the development of new nonaddictive, therapeutic agents for chronic pain management, which is an urgent unmet medical need to be tackled by NIH's Helping to End Addiction Long-term (HEAL) initiative. We recently discovered that nerve injury induced concurrent upregulation of the calcium channel alpha-2-delta-1 subunit (CaV21) and thrombospondin-4 (TSP4) proteins in sensory and spinal cord neurons that contributes to neuropathic pain development by inducing aberrant excitatory synapse formation and sensitization of neurotransmission in spinal cord. We have identified a target side in the TSP4 that plays a critical role in mediating these pathological changes upon interaction with the CaV21 protein. To validate this novel target site for development of nonaddictive pain medications, we plan to use multidisciplinary approaches, involving three independent laboratories, to investigate if blocking and genetic deletion of the target site can block/prevent (Aim 1) pain state development; (Aim 2) aberrant excitatory synapse formation; (Am 3) spinal cord neuron sensitization after injury in two neuropathic pain models. Successful completion of this project will provide important information for further development of specific therapeutic medications for neuropathic pain management as inspired and supported by the HEAL initiative.

项目摘要/摘要 验证新的疼痛靶点是开发新的疼痛靶点的关键一步 非上瘾的治疗药物，用于慢性疼痛管理，这是一个紧急的未得到满足的问题 医疗需要通过NIH的帮助结束成瘾长期(Hear)倡议来解决。 我们最近发现，神经损伤导致钙离子同时上调。 感觉中的通道α-2-β-1亚单位(Cav21)和血栓反应蛋白4(TSP4)蛋白 和脊髓神经元通过诱导产生神经病理性疼痛 脊髓异常兴奋性突触形成与神经传递敏化。 我们已经在TSP4中确定了在调解这些问题方面发挥关键作用的目标方面 与CAV21蛋白相互作用后的病理变化。为了验证这个新的目标 开发非成瘾性止痛药的网站，我们计划使用多学科 方法，涉及三个独立的实验室，以调查是否阻断和遗传 目标位置的删除可以阻止/防止(目标1)疼痛状态的发展；(目标2)异常 兴奋性突触形成；(AM 3)损伤后脊髓神经元敏化 神经病理性疼痛模型。该项目的成功完成将提供重要的 进一步开发治疗神经病理性疼痛的特定治疗药物的信息 在Hear倡议的启发和支持下进行管理。