研究表明促进神经再生可有效改善缺氧缺血性脑损伤（HIBD）后神经功能。我们曾率先报导左旋半胱氨酸（经CBS催化生成内源性H2S）能促进神经干细胞（NSC）增殖分化，但其在HIBD中的作用及机制不详。最近我们发现左旋半胱氨酸可上调NSC中Shh表达，并促进HIBD新生小鼠海马NSC增殖，改善其认知功能；而我们建立的NSC特异性Shh基因敲除(NestinCre/Shhflox/flox)小鼠HIBD后海马NSC增殖降低，且左旋半胱氨酸对其疗效不佳。由此我们推断内源性H2S通过激活Shh通路诱导海马神经再生，促进HIBD后神经功能恢复。本课题拟首次构建NSC特异性CBS基因敲除小鼠(NestinCreERT2/CBSflox/flox)，观察内源性H2S对HIBD后神经再生的影响及其与Shh通路的关系，阐明左旋半胱氨酸在HIBD中的三级预防策略，为探讨HIBD治疗新策略提供实验依据和动物模型。

Studies have demonstrated that the neurogenesis after hypoxic-ischemic brain damage (HIBD) contributes to functional recovery. Endogenous H2S is mainly generated in brain by cystathionine β synthase (CBS) from L-cysteine. We have reported that NSCs expressed CBS and produced H2S. And addition of endogenous H2S donor, L-cysteine, stimulated proliferation and increased the differentiation potential of NSCs to neurons. However, the role of endogenous H2S in HIBD is unclear. Recently, we found that L-cysteine increased the Shh expression in NSC. Additionally, L-cysteine promoted proliferation of NSC in the DG of hippocampus, and improved the learning and memory performance in HIBD mice. Moreover, it has been demonstrated that the proliferation of NSC in the hippocampus was decreased, and L-cysteine has no obvious effect on proliferation of NSC in the same brain region in the NSC special Shh-deficient mice (NestinCre/Shhflox/flox) following HIBD. Arising from this, we hypothesized that endogenous H2S promotes hippocampal neurogenesis in neonatal mouse following HIBD by activating Shh pathway, and played a neuroprotective role in HIBD. To test the relationship of endogenous H2S and hippocampus neurogenesis in neonatal mouse following HIBD, we would set up the inducible NSC special CBS-deficient mice (NestinCreERT2/CBSflox/flox ) and investigate the underlying mechanisms of L-cysteine in three steps of preventive strategy of HIBD, via Shh pathway. This project will disclose new insights into therapeutic method in HIBD and provide new animal models.