星形胶质细胞向A1型极化释放C3通过下调UCHL1抑制qNSC激活对脊髓神经再生的阻抑机制研究

脊髓损伤（SCI）是灾难性疾病目前尚无有效疗法。内源性神经干细胞（NSC）无免疫排斥而备受关注。如何激活内源性静息NSC(qNSC)分化为神经元修复SCI是科学难题。预实验表明，SCI后泛素水解酶（UCHL1）被抑制，qNSC中冗余蛋白累积；而在激活态NSC高表达可清除冗余蛋白激活qNSC向神经元分化。上调SCI后UCHL1水平可促进qNSC激活和神经再生。检测SCI微环境发现星形胶质细胞向A1型极化产生C3抑制qNSC激活。科学假说：SCI致星形胶质细胞向A1型极化产生C3抑制NSC中UCHL1，阻碍qNSC中冗余蛋白清除，抑制NSC激活及修复SCI。本项目研究C3抑制Nrf2/UCHL1通路及对下游蛋白酶体亚基作用机制，特异中和抗体阻断星形胶质细胞A1型极化，用LV-UCHl1转染NSC提高UCHL1蛋白水平，清除qNSC冗余蛋白激活NSC促神经再生的机制研究，为SCI治疗提供新思路。

Spinal cord injury (SCI) is a catastrophic disease with no effective treatment currently. Endogenous neural stem cells (NSCs) have attracted much attention due to no immune rejection. How to improve the microenvironment and activate endogenous quiescent NSC (qNSC) to differentiate into neurons to repair SCI is the key problem. Our experiments showed that ubiquitin hydrolase (UCHL1) level was reduced after SCI, resulting in aggresome accumulated in qNSC. However, it was highly expressed in activated NSC and could clear aggresome to activate qNSC to differentiate into neurons. Overexpression of UCHL1 after SCI promoted qNSC activation and nerve regeneration. Analysis of the SCI microenvironment revealed that astrocytes were polarized towards A1 type, and released C3 to inhibit qNSC activation. Thus, we put forward the hypothesis that astrocytes are polarized to A1 type post-SCI, which releases C3 inhibits UCHL1 levels in NSCs, preventing the removal of aggresome in qNSCs and inhibiting NSC activation to repair SCI. In this study, we intend to use the specific neutralizing antibodies to block astrocytes from polarizing to type A1, which restores UCHL expression and clears the aggresome in qNSC to activate its differentiation into neurons, and promote SCI repair; and the role of C3/C3R in UCHL1 and its downstream proteasome subunits will be further illustrated. Our study will provide new ideas for SCI treatment.