LRRC8A与NMDA受体的相互作用及其对神经病理性疼痛的调节和机制研究

富含亮氨酸重复序列蛋白家族8A（LRRC8A）是容积调节氯通道的唯一必需亚单位，对细胞容积及生理功能的调节至关重要，并与多种疾病发生发展有关。然而，LRRC8A能否影响神经病理性疼痛及对NMDA受体的具体调控机制尚不清楚。文献和我们前期研究工作表明LRRC8A下调增强了脊髓背角神经元突触前和突触后NMDA受体活性，从而导致NMDA受体依赖性痛觉过敏的发生。我们推测，LRRC8A与NMDA受体的相互作用解除后，促进NMDA受体的突触转运，导致膜表面NMDA受体的异常表达，从而引发神经病理性疼痛。本项目我们将利用基因敲除小鼠模型、临床数据及样本和多种技术手段，确证LRRC8A与神经病理性疼痛的关系及其分子机制以及潜在的治疗手段，研究LRRC8A与NMDA受体是否存在直接相互作用及关键位点。该项目的开展是基础研究和临床研究的很好结合，将为神经病理性疼痛的研究和治疗提供新的靶点和神经生物学依据。

Leucine-rich repeat containing 8A (LRRC8A) is the only necessary subunit of the volume regulated chloride channel, which plays an important role in the regulation of cell volume and physiological function, and is related to the occurrence and development of various diseases. However, whether LRRC8A can affect neuropathic pain and the specific regulatory mechanism of NMDA receptor is unclear. The literature and our previous work showed that the down-regulation of LRRC8A enhanced the presynaptic and postsynaptic NMDA receptor activity in spinal dorsal horn neurons, which led to the occurrence of NMDA receptor dependent hyperalgesia. We speculate that after the interaction between LRRC8A and NMDA receptor is relieved, it can promote the synaptic transport of NMDA receptor, and lead to the abnormal expression of NMDA receptor on the membrane surface, thus causing neuropathic pain. In this project, we will use gene knockout mouse model, clinical data, samples and various technical means to confirm the relationship between LRRC8A and neuropathic pain, its molecular mechanism and potential treatment measures, and study whether there is direct interaction and key site between LRRC8A and NMDA receptor. The project is a good combination of basic research and clinical research, which will provide new targets and neurobiological basis for the research and treatment of neuropathic pain.