基于CRISPR系统编辑APP基因的阿尔茨海默疾病干细胞移植效果评估研究

Alzheimer's disease (AD) is a common neurodegenerative disorder. In recent years, the number of AD patients is rapid growth around the world, but the mechanism of AD is still not clear and there is no cure. The coding mutation (A673T) in the APP gene protects against Alzheimer’s disease and cognitive decline, which reducing the β-cleavage of APP. Our previous work showed that the expression of Aβ42 was reduced and against the damage of synaptic in APP A673T cells. In this project, we will use APP/PS1 transgenic mice as the disease model. In the first part of this project, we will apply the iPSCs that derive from mouse skin fibroblasts, where edit the APP to A673T. In the second part, we will convert the edited iPSCs to neural stem cells and transplant them into the brain of AD mice. Then behavior experiments and pathologic analysis will be performed to determine the effect of the gene therapy and stem cell therapy on AD. Finally, we will provide new treatments for AD. This project is a research of Translational Medicine, which will provide important clues and experiment data for novel therapy and prevention targets for Alzheimer’s disease.

阿尔茨海默疾病（AD）是最常见的神经退行性疾病。近年来患病人数在全球范围内快速增长，但其发病机制尚未明确，也无有效的治疗手段。APP的突变能够影响β淀粉样蛋白的成熟，因此携带A673T突变的APP基因的人群不易患阿尔茨海默疾病。我们的前期研究显示，在APP A672T的神经元细胞中，Aβ42的生成显著减少，其对毒性的耐受作用显著增强。本项目拟以经典的APP/PS1转基因AD小鼠模型为对象，进行三部分研究：第一部分，通过对小鼠皮肤成纤维来源的iPS细胞进行基因编辑，构建APP A673T突变；第二部分，通过诱导编辑后的iPS细胞转化为神经干细胞，并将其移植回AD小鼠大脑。第三部分，通过行为学实验及病理分析，验证突变的神经干细胞对认知及病理的改善作用，评估移植效果，分析治疗方案的潜力。本项目是一项以满足阿尔茨海默临床实际治疗需求的转化医学研究，将对AD的治疗提供新的线索和实验数据。

阿尔茨海默疾病（AD）是最常见的神经退行性疾病之一，但其发病机制尚未明确，也无有效的治疗手段。研究表明，APP基因A673T突变能够影响β淀粉样蛋白的成熟，自然人群中携带该突变基因的人患AD的风险显著降低。本项目以APP基因A673T突变为切入点，证明了APP基因A673T突变可以有效抑制Aβ42寡聚体的形成，明确了APP基因A673T突变在AD疾病进程中的保护性作用。同时，建立了APP基因A673T突变技术体系，实现在多细胞模型中高效稳定的进行细胞突变编辑，进一步建立了IPS细胞APP基因A673T突变的基因编辑方法。最后，对基因编辑系统CRISPR/Cas9在细胞治疗领域的应用的安全性进行了分析。本项目将对阿尔茨海默疾病细胞治疗提供理论基础及技术方案的补充。

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