Resveratrol联合MSCs移植对阿尔茨海默鼠的干预效果及Sirt1分子信号的介导作用

项目名称： Resveratrol联合MSCs移植对阿尔茨海默鼠的干预效果及Sirt1分子信号的介导作用

项目编号： No.81471306

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： 关方霞

作者单位： 郑州大学

项目金额： 80万元

中文摘要： 阿尔茨海默病(AD) 是中枢神经系统退行性变，目前无有效疗法。课题组前期发现，脐带源性MSCs移植能改善AD鼠症状，但干细胞在脑内存活和定向分化为神经元的效率低，细胞转归和疗效提高是亟需解决的关键问题。Sirt1基因能调控细胞寿命，Resveratrol可激活Sirt1，然而对AD的干预效果报道不一。本研究拟通过体外实验观察Resveratrol对脐带MSCs和不同月龄AD鼠神经干细胞增殖、分化、衰老影响的量效关系，Sirt1及相关分子p16、p53、p21、pCNA表达；体内研究Resveratrol联合MSCs移植对不同月龄AD鼠脑内Aβ沉积、学习记忆能力、干细胞存活、增殖、分化， MRI活体示踪及Sirt1分子信号作用。该研究提出Resveratrol联合MSCs移植调控干细胞微环境，重塑细胞命运的理论假设，并有助于明确干预效果和Sirt1分子的作用机制，为AD防治提供科学依据。

中文关键词： 阿尔茨海默病；Resveratrol；干细胞移植；Sirt1分子信号；转基因鼠

英文摘要： Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory and cognitive impairment and changes in behavior. There has been no effective therapy till now. stem cell transplantation is promising for AD treatment. We previously showed that transplantation of umbilical cord derived mesenchymal stem cells (MSCs) to AD mice could ameliorate clinical systom ,improve the ability of learning and memory and reduce β-amyloid deposition. However, the rates of cell survival and neuronal differentiation were pretty low. It is critical to promote the cell fate of stem cells and efficacy. Sirt1 gene, which plays an important role in regulating the lifespan and aging of cells, can be actived by Resveratrol. Although Resveratrol possesses diverse biochemical and physiological properties, its neuroprotective benefits in animal models of AD were still controversial. Considering the inconsistent results, It is necessary to determine the exact role of Resveratrol on AD. In this study, we will examine the effect of Resveratrol with different doses on cell survival，proliferation, differentiation and senencense by isolating umbilical cord derived MSCs and neural stem cells (NSCs) from different ages of AD trangenic mice. The expression of Sirt1 and related molecules p16、p53、p21、pCNA will be detected by real time PCR and Western blot. Different ages of AD mice were divided into groups to investigate Aβ deposition, learning and memory ability,stem cell survival, proliferation and differentiation, Sirt1 signaling molecules in the brain. Also,MRI in vivo monitoring after stem cell transplantation will be compared with neural behavior tests. This study present a theoretical hypotheis about Resveratrol combining MSCs transplant to improve cell fate and efficacy, which will contribute to clarify the intervention effect of Resveratrol on AD, also illuminate the mechanism of Sirt1 signaling pathway mediating the process, which will provide scientific bases and strategy for AD therapy.

英文关键词： Alzheimer's disease;Resveratrol;stem cell transplantation;sirt1 signaling pathway;transgenic mice