我们前期发现化学小分子、激素等对脊髓损伤（SCI）疗效有限；间充质干细胞（MSC）有望治疗SCI，但体外扩增易衰老、质量不稳定限制了其临床应用。现有抗MSC衰老方法如小干扰RNA下调促衰老因子p21，起效慢，不适于翻译迟缓的衰老细胞，且可能扰乱核酸。Trim-Away是基于三结构域蛋白TRIM21直接降解胞内蛋白的技术，可迅速激活抗衰老通路，且不影响核酸。我们已纯化TRIM21、抗p21抗体，已分析大鼠SCI后22个炎症因子时序变化。故我们用Trim-Away快速降解p21以促MSC修复SCI，并探讨机制。我们拟体外确证Trim-Away快速降解p21抗MSC衰老的有效性和安全性；通过组织立体结构和神经功能研究其对大鼠SCI的作用；通过系统分析MSC对SCI局部45种细胞因子的调节等功能，探讨其影响MSC修复SCI的机制。本项目将推动MSC治疗SCI的临床转化，对其它细胞治疗研究也有借鉴。

Previously we found that the chemical small molecules, hormones and so on have limited therapeutic effects on spinal cord injury (SCI). Mesenchymal stem cell (MSC) treatment hold the promise to heal SCI, but the tendency of senescence and the instability of quality upon expansion limits its clinical applications. Current strategies against the senescence of MSC, such as the small interfering RNA to downregulate the pro-senescent factor p21, have slow onset and are not suitable for senescent cells whose translation is inactive. Moreover, they have the risk of disturbing nucleic acids. Based on tripartite motif-containing protein 21 (TRIM21), Trim-Away is a new technology for rapid degradation of endogenous proteins and quick activation of anti-senescence signaling pathways. It is suitable for senescent cells whose translation and division is inactive, and capable to degrade long-life and abundant proteins. It also has better specificity and avoids disturbing nucleic acids, hence has a higher safety level. We have synthesized and purified TRIM21 and anti-p21 antibody, and have analyzed the changes of 22 inflammatory factors after rat SCI. Therefore, we take the lead to use Trim-Away to rapidly degrade p21, and hence promote MSC treatment of SCI. We will then also study the underlying mechanisms. We will ① study the efficacy and safety of that rapid degradation of p21 by Trim-Away inhibits MSC senescence; ② study its effects on rat SCI through analysis of three-dimensional tissue structure and sensorimotor function; ③ study the underlying mechanisms how rapid degradation of p21 by Trim-Away affects MSC therapy of SCI, through systematical analysis of MSC functions including secretion of various cytokines and regulation of local 45 cytokines in SCI. We may promote clinical translation of MSC therapy of SCI. This study may also be of great referential significance for future research on stem cell biology and cell therapy.