PTEN和ChABC双基因干预的脂肪间充质干细胞移植治疗大鼠急性脊髓损伤的疗效及机制研究

项目名称： PTEN和ChABC双基因干预的脂肪间充质干细胞移植治疗大鼠急性脊髓损伤的疗效及机制研究

项目编号： No.81472073

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 吴建煌

作者单位： 中南大学

项目金额： 70万元

中文摘要： 急性脊髓损伤（SCI）现有的治疗方法多不理想。申请者在以往研究基础上，提出用PTEN及ChABC双基因干预的脂肪间充质干细胞移植治疗SCI。PTEN 是抑癌基因，通过RNAi沉默PTEN 基因，可增强移植细胞在缺血缺氧微环境中的存活、扩增和分化能力，消除神经再生的内部抑制因素；硫酸软骨素酶ABC（ChABC）可降解胶质瘢痕的主要成分硫酸软骨素蛋白多糖（CSPGs），通过慢病毒介导使ChABC基因过表达，可减轻胶质瘢痕的阻碍，畅通神经通路，消除了影响神经功能的外部因素。同时，由于siRNA转染不稳定，PTEN基因沉默具有暂时性，避免了肿瘤形成；而慢病毒可使ChABC基因获得长期稳定表达，有利于发挥长期的瘢痕抑制作用，且不影响胶质细胞释放神经营养因子。本研究阻断内源及外源抑制因素，发挥协同作用，同时联合基因治疗和细胞治疗，更有效地促进SCI后的神经康复。

中文关键词： 脊髓损伤；脂肪间充质干细胞；PTEN基因；ChABC基因；干细胞移植

英文摘要： Existing treatments of acute spinal cord injury are often unsatisfactory. On the basis of previous research, we propose to use PTEN and ChABC double genes intervention on Adipose-Derived Stem Cells transplant to cure acute spinal cord injury. PTEN is Tumor Suppressor Gene. If PTEN gene silencing by RNAi, the survival ability, expansion and differentiation of transplanted cells could be enhanced in the hypoxic microenvironment, which could eliminate the internal factors of nerve regeneration. Chondroitinase ABC could degrade chondroitin sulfate proteoglycans（CSPGs）which is the main component of glial scar. By lentivirus-mediated overexpressed ChABC genes, obstruction of glial scar could be relieved, which could eliminate the external factors of nerve reconstruction. Meanwhile, as the unstable of siRNA, the silence of PTEN is temporary, which could avoid tumor formation. While the lentivirus-mediated overexpressed ChABC could be long-term and stable expression and not avoid glial cells release neurotrophins. In this study, blocking the inhibition of endogenous and exogenous factors could play synergy, promote more effective neurological rehabilitation after SCI. Combined gene therapy and cell therapy could also show more advantages.

英文关键词： spinal cord injury;adipose derived stem cell;PTEN gene;ChABC gene;transplantation