POSTN调控TGF-β1信号通路促进缺氧缺血后神经干细胞增殖分化的机制

Hypoxic-ischemic encephalopathy is one of the most common reasons of neonatal death and disability. The plasticity of the immature brain is good. Repairing brain injury can significantly improve the prognosis through the endogenous activation of proliferation and differentiation of stem cells. We have found in pilot studies that POSTN participated in the regulation on proliferation and differentiation of neural stem cells, but the mechanism was unclear. This project is to establish the oxygen-glucose deprivation models in vitro based on the POSTN-knockout mice. Our objectives are:(1) To explore whether POSTN can promote neural stem cell proliferation and differentiation by modulating TGF-β1 pathway,and to identify the role of this signaling pathway by modulating TGF-β1.(2) To study whether POSTN can impact on the activity of TGF-β1 signaling pathway during the proliferation and differentiation of neural stem cells, including the expression of its downstream genes.(3) To study whether POSTN-knockout mice can promote the proliferation and differentiation of neural stem cells by modulating TGF-β1 signaling pathway so as to protect neural system. To identify the hypothesis if POSTN can promote the proliferation and differentiation of neural stem cells by TGF-β1 signaling pathway to repair neonatal hypoxic-ischemic brain injury, so as to supply a new treatment strategy for the newborn hypoxic-ischemic brain injury.

缺氧缺血性脑病是新生儿致死和致残主要原因之一，未成熟脑可塑性强，通过内源性激活干细胞增殖分化修复脑损伤可显著改善预后。本课题组前期研究发现并证实POSTN参与调控神经干细胞的增殖分化，但机制未明。本课题利用已获得的POSTN基因敲除小鼠，建立体外氧糖剥夺模型，研究：（1）TGF-β1信号通路对缺氧缺血后神经干细胞增殖分化的影响，并对TGF-β1信号通路进行调控，进一步验证该信号通路在神经干细胞增殖分化中的作用。（2）神经干细胞增殖分化过程中POSTN对TGF-β1信号通路活性的影响，包括对其下游基因的表达影响。（3）研究POSTN基因缺失小鼠中是否可以通过调节TGF-β1信号通路来促进神经干细胞的增殖与分化从而达到促进神经保护的作用。明确TGF-β1信号通路是否参与POSTN促进缺氧缺血后神经干细胞增殖分化过程这一研究假说，为新生儿缺氧缺血性脑损伤提供新的治疗策略。

POSTN蛋白是一种细胞外基质蛋白，在多种细胞存活、迁徙和再生中起着重要的作用，但在神经系统中的作用鲜少受到关注。本研究的目的是明确在缺氧缺血性脑损伤后POSTN在神经干细胞增殖分化中的作用。我们发现在mRNA水平上，POSTN的表达在神经干细胞分化后有显著性增加。POSTN基因敲除与新生小鼠DG区神经干细胞增殖分化密切相关。此外，神经干细胞培养时加入POSTN有显著的促进神经干细胞增殖以及分化为神经元和星形胶质细胞的作用。通过新生大鼠侧脑室注射外源性补充POSTN蛋白，可以观察到缺氧缺血性脑损伤后7天和14天分别有效地促进了SVZ区和DG区的神经干细胞增殖分化。这些结果表明POSTN蛋白作为内环境重要的分子参与神经干细胞增殖和分化，参与缺氧缺血性脑损伤后神经再生和修复。因此，对POSTN的深入研究，对于探寻新生儿缺氧缺血性脑损伤的治疗策略具有重要的意义。