硒蛋白P干预阿尔茨海默症的机制探讨

硒蛋白P (SelP)对机体特别是脑内硒的内稳态至关重要，并发挥着调节体内氧化还原平衡的作用。最近有研究指出，SelP可能与阿尔茨海默症（AD）相关，干预AD的发生、发展，但其作用机制尚不清楚。本项目从分子、细胞和动物三个层面上研究SelP与多种AD相关分子的相互作用及对多种AD相关指标的影响，以期阐明SelP在AD中的功能及可能的分子机制。主要研究内容包括：1) SelP结合AD相关金属离子的性质及对金属离子内稳态和氧化应激的影响; 2) SelP对AD相关细胞的作用及AD相关指标的变化和分子机理; 3) 以AD模型鼠研究SelP对小鼠学习、认知和运动能力的影响。本项目的另一主要研究内容是以外源tRNAEF-Tu指导Sec定点、高效插入到蛋白序列中，实现SelP-N端结构域的大量制备，并对其结构和性质进行表征，完成该蛋白构效关系的研究，为该蛋白的深入研究和有效应用提供基础。

Among the 25 selenoproteins found in human, selenoprotein P (SelP) is unique that contains multiple selenocysteine in sequence. SelP is central to the selenium homeostasis in human, especially in the brain. Besides, this protein also plays important roles in regulating the cellular redox status. Recently, SelP was found to be involved in Alzheimer's disease (AD), interfering the onset and progression of this disorder, however, the molecular mechanism of which is far away from clear. In this project, the potential roles of SelP in AD as well as the underlying mechanisms will be explored at the molecular, cellular and organismal levels. The interactions between SelP and several AD-related molecules will be studied. Three parts will be included in this project: 1) Metal binding properties of SelP and the roles of SelP in the homeostasis of metal ions and redox; 2) Effects and mechanisms of SelP on AD relevant cells and AD pathological features; 3) Effects of SelP expression on the learning and cognitive abilities of AD transgenic mouse. In addition, the N-ternimus of SelP (SelP-N) in great quantity will be prepared, with the aid of tRNAEF-Tu, an exogenous Sec tRNA that can be recognized by the elongation factor EF-Tu. The structure and properties of SelP-N will be extensively characterized. This project will provide elementary data for elucidating the molecular mechanism of SelP in preventing Alzheimer's disease.