Vit A双向调节Wnt/β-catenin 信号影响HIBD后大鼠海马神经干细胞增殖的应用机制研究

Hypoxic ischemic brain damage (HIBD) is a high incidence and poor treatment disease of the nervous system in neonatal period. Vitamin A deficiency (VAD) is a global nutrition deficiency disease. From our youth natural science projects, we first found the children with HIBD show high incidence and severe degree of VAD, and reveal the VA nutrition can affect the prognosis of neurological function after HIBD. RA via RARs activated the PI3K--AKT signal to inhibit the neuronal apoptosis is the possible mechanism. But the effect on cell proliferation after HIBD is unclear. Our early data revealed the VA nutrition can promote the proliferation of hippocampal NSC after HIBD, and up regulate the expression of Wnt/β-catenin target gene. However, we recognized that VA signaling down-regulate the Wnt/β-catenin signaling and play cell proliferation inhibition in tumor, neural developmental from the comprehensive literature. So we assume that the VA signal can two-ways regulate Wnt/β-catenin signaling to affect cell proliferation, it depends on the VA signal intensity influence the balance between endochylema AKT---GSK-3β and nuclear β-catenin activation. These information also indicate VA therapy may have a dose window in HIBD.we tried to advance the study based the former Youth Natural Science Foundation, in-depth study the effect and mechanism of VA regulating NSC proliferation after HIBD.

缺氧缺血脑损伤（HIBD）是新生儿期高发神经疾病，治疗手段有限预后不良。维生素A缺乏（VAD）是全球性营养缺乏病，前自科项目首次发现HIBD患儿VAD呈高发且程度重并揭示VA营养影响HIBD的神经功能预后，可能机制是RA通过RARɑ激活PI3K--AKT信号影响神经元凋亡。但对HIBD后细胞增殖的影响尚不明确。前期发现VA促进HIBD后海马NSC增殖，并上调Wnt/β-catenin靶基因的表达。但文献发现VA信号在肿瘤，神经发育中下调Wnt/β-catenin进而抑制细胞增殖。就此假设VA信号可双向调节Wnt/β-catenin信号来调节细胞增殖，方向性可能取决不同VA信号强度影响的胞内AKT---GSK-3β激活与核内β-catenin激活之间的平衡。故提示在HIBD中可能有VA治疗剂量窗。就此我们试图在前一青年自科基础上推进此研究，深入探讨VA营养对HIBD后神经细胞增殖作用及机制，

缺氧缺血脑损伤（HIBD）是新生儿期高发神经疾病，治疗手段有限预后不良。维生素A缺乏（VAD）是全球性营养缺乏病，前自科项目首次发现HIBD患儿VAD呈高发且程度重并揭示VA营养影响HIBD的神经功能预后，可能机制是RA通过RARɑ激活PI3K--AKT信号影响神经元凋亡。但对HIBD后细胞增殖的影响尚不明确。前期发现VA促进HIBD后海马NSC增殖，并上调Wnt/β-catenin靶基因的表达。但文献发现VA信号在肿瘤，神经发育中下调Wnt/β-catenin进而抑制细胞增殖。就此假设VA信号可双向调节Wnt/β-catenin信号来调节细胞增殖，方向性可能取决不同VA信号强度影响的胞内AKT---GSK-3β激活与核内β-catenin激活之间的平衡。故提示在HIBD中可能有VA治疗剂量窗。我们通过神经干细胞体外实验发现VA的体内活性代谢物RA在1-5umol/L浓度能明显促进缺氧缺糖损伤后神经干细胞增殖，并且揭示其信号通路是RARɑ------AKT-----GSK3β-----β-Catenin-----Cyclin-D1，并进一步揭示浓度的差异可以双向影响此信号通路的激活，从而影响