PTPσ源性多肽修复脊髓损伤的分子机制研究

The cure of spinal cord injury remains elusive, and the key is axon regeneration in central nerve system. PTPσ, the receptor of axon growth inhibitor, plays a key role in the regulation of axon regeneration. Our previous work proved that PTPσ-targeted therapy could effectively promote axon regeneration and repair spinal cord injury. In 2015, it was reported that peptide derived from PTPσ effectively induced axon regeneration and enhanced function of injured rat spinal cord. However, the molecular mechanism of this peptide is unclear, and therefore development of this drug in neural repair is suspended. Based on structural simulation, we proposed a hypothesis that PTPσ-derived peptide interacts with PTPσ D1 domain and blocks the phosphatase active center of drug target. We aimed to test this hypothesis via structural biology technique to elucidate the molecular mechanism of drug-target interaction. Then we will modify the peptide structure to enhance drug potency. The modified peptide will be evaluated on three levels: molecular level to test drug's interaction with PTPσ，cellular level to verify axon regeneration, and animal level to assess the therapeutic effect using rat spinal cord injury model. Based on researcher's experience on peptide drug and previous work on PTPσ-targeted gene therapy on spinal cord injury, this study focus on PTPσ-targeted drug, systematically elucidate the mechanism of drug and modified the drug and conduct drug screening. This project is of high theoretical and practical importance on neural repair therapy.

脊髓损伤修复的瓶颈在于中枢系统的轴突再生。PTPσ是轴突生长抑制因子受体，对轴突再生起关键调控作用。本团队前期已证实靶向PTPσ修复脊髓损伤的有效性。2015年，研究者发现PTPσ源性多肽可以有效促进轴突再生，改善大鼠脊髓损伤后功能，具有作为脊髓损伤修复药物的应用前景，但缺乏进一步分子机制研究。基于结构模拟，申请人提出多肽通过结合PTPσ的D1结构域，特异性封闭靶点磷酸酶活性中心的机制假说。本课题拟通过结构生物学手段进行验证，阐明药物与靶点相互作用的分子机制。拟在此基础上优化多肽并在三个层次进行评价：分子水平验证靶点结合强度、细胞水平验证促进轴突再生作用及动物水平利用大鼠脊髓损伤模型评价多肽的修复作用。本研究聚焦PTPσ靶向药物，基于申请人丰富的多肽药物研究经验及前期靶向PTPσ修复脊髓损伤的工作基础，系统地进行机制探索、药物优化和药效评价，对于脊髓损伤修复有重要的理论意义和应用前景。

本课题聚焦脊髓损伤的病理机制及药物干预。PTPσ源性多肽可以有效促进中枢神经轴突再生，改善大鼠脊髓损伤后功能，具有作为脊髓损伤修复药物的应用前景。为进一步探究其分子机制，首先开展药物-靶点复合物的结构模拟，发现多肽通过结合PTPσ的D1结构域，特异性封闭靶点磷酸酶活性中心的机制。本研究利用结构生物学手段进行验证，阐明药物与靶点相互作用的分子机制。在此基础上优化多肽并在细胞水平验证促进轴突再生作用及动物水平利用大鼠脊髓损伤模型评价多肽的修复作用。本团队在脊髓损伤病理机制的研究中，发现铁死亡是脊髓损伤继发性损伤阶段的重要机制，使用铁死亡抑制剂可以有效修复大鼠脊髓损伤，本研究是对脊髓损伤微环境失衡理论的深入和扩展，也为修复提供了新的策略。本课题在重要国内外期刊发表脊髓损伤研究论文数篇，其中一篇被Neuroregeneration Research 杂志评为年度最受关注论文。研究成果受到脊髓损伤及神经再生领域同行关注，被多篇综述作为研究前沿重点介绍。本课题对于神经修复药物探索取得自主知识产权成果，发现一种新的具有脊髓损伤修复活性的化合物，授权中国发明专利和美国发明专利。本课题取得的成果对于脊髓损伤修复有重要的理论意义和具有临床转化价值的新化合物。