在泛素连接酶（ubiquitin ligases）的作用下，泛素分子（ubiquitin）转移到底物蛋白的赖氨酸（Lysine）残基上，引导蛋白发生内吞、降解等过程。泛素化修饰是突触传递效率的重要调节方式。脊髓背角表达多种泛素连接酶。但泛素化修饰与痛觉敏化的关系仍不清楚。申请人在前期的研究中发现：与病理性疼痛密切相关的NMDA受体GluN2B亚基，能够特异性结合一种泛素连接酶——Casitas B-lineage lymphoma b（Cbl-b）。Cbl-b介导的泛素化，控制着GluN2B的突触表达，抑制GluN2B介导的痛觉突触传递；打断Cbl-b与GluN2B的相互作用，可能是外周神经损伤诱发GluN2B依赖性痛觉敏化的重要因素。本项目拟在痛觉传递的关键性Somatostatin阳性神经元中，深入研究Cbl-b泛素化GluN2B的分子机制及其病理学意义。

The ubiquitin ligases catalyze the transfer of ubiquitin to the Lysine residues on substrate proteins, leading to the protein endocytosis and degradation. The ubiquitin modification is important for the regulation of synaptic efficacy. Several ubiquitin ligases are expressed in spinal cord dorsal horn. However, the relationship between ubiquitination and spinal sensitization of painful responses remains to be elucidated. Our preliminary experiments found that NMDA receptor GluN2B subunit, one of the critical players in neuropathic pain, specifically bound to ubiquitin ligase Casitas B-lineage lymphoma b (Cbl-b). The ubiquitin modification by Cbl-b might control synaptic GluN2B expression and inhibit the pain transmission mediated by GluN2B. Disruption of Cbl-b interaction with GluN2B might serve as an important way for peripheral nerve injury to cause GluN2B-dependent allodynia. This project aims to study the mechanisms and significance of Cbl-b-mediated GluN2B ubiquitination in pain-transmitted somatostatin-positive neurons.