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.

项目总结/摘要 新的疼痛靶点的验证是开发新的疼痛靶点的关键一步。 非成瘾性，治疗药物的慢性疼痛管理，这是一个迫切的未满足的 美国国立卫生研究院的帮助结束成瘾长期（HEAL）倡议。 我们最近发现，神经损伤诱导同时上调钙 通道α-2-δ-1亚单位（CaV α 2 β 1）和血小板反应蛋白-4（TSP 4）蛋白在感觉神经元中的表达 和脊髓神经元，其通过诱导 脊髓异常兴奋性突触形成和神经传递敏化。 我们已经在TSP 4中确定了一个目标侧，它在介导这些过程中起着关键作用。 与CaV β 2 β 1蛋白相互作用后的病理变化。为了验证这个新目标 网站的非成瘾性止痛药的发展，我们计划使用多学科 涉及三个独立实验室的方法来调查阻断和遗传是否 靶位点的缺失可以阻断/预防（目的1）疼痛状态的发展;（目的2）异常疼痛状态的发展;（目的3）疼痛状态的发展;（目的4）疼痛状态的发展;（目的5）异常疼痛状态的发展;（目的6）异常疼痛状态的发展;（目的7）异常疼痛状态的发展;（目的8）异常疼痛状态的发展。 兴奋性突触形成;（Am 3）两个损伤后脊髓神经元敏化 神经性疼痛模型。该项目的成功完成将提供重要的 进一步开发神经性疼痛特异性治疗药物的信息 管理的启发和支持的愈合倡议。