BMSCs调控脊髓损伤中神经元mitoUPR的作用及其机制研究

如何有效促进脊髓损伤后神经元的存活一直是脊髓损伤研究领域的重点。近期研究表明，如果机体受到持续严重的损伤，线粒体内变性或者错误折叠的蛋白质不能被及时降解而大量积聚，就会通过线粒体的未折叠蛋白反应(unfolded protein response, mitoUPR)，诱导细胞凋亡，加重细胞的不可逆损伤。我们前期研究发现，脊髓损伤后早期阶段有mitoUPR产生，其标记分子热休克蛋白HSP60表达显著增加；体外将骨髓间充质干细胞（BMSCs）与损伤神经元共培养，发现BMSCs可以将线粒体转移给损伤神经元，减轻神经元的mitoUPR反应程度，减少神经元死亡。在此基础上，我们拟深入研究转录因子Ap-1/CHOP介导的mitoUPR在脊髓损伤中神经元凋亡中的作用及其上下游信号途径，并进一步阐明BMSCs通过线粒体转移改善mitoUPR途径，促进脊髓损伤修复再生的效应及靶分子机制。

The severity of secondary injury after spinal cord injury is critical for structural and functional recovery in the later stage of spinal cord injury. Promoting the survival of injured neurons is beneficial to the recovery of structure and functional recovery after spinal cord injury. Recent studies have shown that if mitochondrial degeneration or misfolded proteins are accumulated, mitochondria initiate mitochondrial unfolded protein response (mitoUPR) in order to maintain protein balance. If the body is subjected to severe damage, apoptosis will be induced by mitoUPR, which will aggravate the irreversible damage of the neurons. Our previous study found that mitoUPR was produced in the early stage of spinal cord injury, and the expression of the molecular marker HSP60 was increased. Bone marrow mesenchymal stem cells (BMSCs) were co-cultured with injured neurons in vitro, and BMSCs were found to transfer mitochondria to injured neurons. BMSCs reduced the degree of mitoUPR in neurons and reduced subsequent neuronal death. On this basis, we intend to further study the role of transcription factor Ap-1/CHOP-mediated mitoUPR in neuronal apoptosis in spinal cord injury and its upstream and downstream signaling pathways, and further elucidate the improvement of mitoUPR by BMSCs through mitochondrial transfer. This study will provide valuable theoretical guidance and experimental basis for the transplantation of BMSCs in spinal cord injury.