Nestin-Cre/STAT3 LoxP活体内调控JAK/STAT3通路介导的内源性神经干细胞-星形胶质细胞功能修复脊髓损伤研究

项目名称： Nestin-Cre/STAT3 LoxP活体内调控JAK/STAT3通路介导的内源性神经干细胞-星形胶质细胞功能修复脊髓损伤研究

项目编号： No.81200944

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 朱振中

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： JAK/STAT3通路在脊髓损伤（Spinal Cord Injury，SCI）后依据病程进展而发挥不同作用。早期通过调控损伤反应性星形胶质细胞/神经干细胞的激活而发挥保护作用。后期介导胶质瘢痕的形成，成为阻碍轴突通过的不利因素。因此，通过基因重组技术无时相性单向调节JAK/STAT3通路治疗脊髓损伤效果均不理想。本实验中拟采用Nestin-Cre/STAT3 LoxP条件性基因敲除技术，建立他莫昔芬可调性中枢神经系统特异性STAT3基因敲除动物模型，结合小分子STAT3激动剂，在活体内SCI不同时相可逆性瞬时双向调节JAK/STAT3通路活性，在SCI早期上调STAT3活性，激活内源性星形胶质细胞/神经干细胞增殖；而在后期下调STAT3活性，抑制内外源性神经干细胞向AST分化。基于JAK/STAT3通路本身，从调控内源性神经干细胞活性及抑制胶质瘢痕形成入手，为脊髓损伤修复进行新的探索。

中文关键词： 锂剂；星形胶质细胞；神经干细胞；脊髓损伤；

英文摘要： The JAK/STAT3 transduction pathway plays multi-facial roles in the pathophysiology of spinal cord injury, its activation stimulates the endogenous neural stem cells activity at the early stage while modulate astrogliogenesis afterwards, which is considered to be the barrier for new axons. The complete inhibition of STAT3 function by knocking out strategy would thus neutralize these two distinct effects. We thus hypothesize that the two-way modulation of STAT3 activity depending on different stage would be beneficial for neuro-regeneration after spinal cord injury. By matching the two commercial available transgenic mice, we can creating tamoxifen-inducible K.O of STAT3 gene. Combing with a specific STAT3 agonist, we can activate STAT3 at early stage and suppress its function at late stage of spinal cord injury. We speculate that this combination would reduce astrogliogensis by the greatest extent without affecting its protective roles.

英文关键词： lithium；Astrocytes；neural stem cells；spinal cord injury；