肌醇焦磷脂IP7对tau蛋白异常磷酸化的影响及机制研究

Abnormally hyperphosphorylation of tau protein plays a critical role in the pathogenesis of Alzheimer disease (AD).Drugs targeted on tau protein and treatment strategy to improve insulin signaling pathways are both the hot spots in the AD therapy. Higher inositol phosphates with energetic pyrophosphate bonds have been described more recently and attracts more and more attention. Best characterized is diphosphoinositol pentakisphosphate IP7(5-PP-[1,2,3,4,6]IP5), which modulates numerous physiologic functions including apoptosis and insulin secretion. This project is aim to find the effect of inositol pyrophosphate IP7 on tau hyperphosphorylation and further more about its molecular mechanism and signal transduction process, using animal model construction, cell culture, RNA interference, western blotting and gene transfer techniques, intends to prove that its key synthase IP6K1 is a potential new target to improve the tau protein abnormal hyperphosphorylation of AD disease. This project makes preliminary exploration for the mechanism of AD therapy and provides new ideas for drug design.

tau蛋白分子在神经细胞内异常聚集，是阿尔茨海默病（AD）最关键的病理特征之一。以tau为靶点的药物开发和以改善胰岛素信号传导通路的治疗策略是当今AD病研究领域的前沿和热点。焦磷酸肌醇作为磷脂酰肌醇家族中的新成员，由于参与了机体内大量生理功能的调节而越来越受到关注，其中最具代表性的是肌醇焦磷酯IP7（5-PP-[1,2,3,4,6]IP5)，对机体内的细胞凋亡以及胰岛素分泌具有重要调控作用。本项目拟从新兴研究的焦磷酸肌醇IP7分子入手，通过构建动物模型，细胞培养，RNA干扰，免疫印记，基因转染等技术，在阐明IP7对tau蛋白异常磷酸化影响的基础上，进一步从分子水平探讨这一改变的信号转导过程以及发生机制，拟证实其关键合成酶IP6K1是改善AD病tau蛋白异常磷酸一个可能的新靶点。本项目有助于阐明IP7参与tau蛋白异常磷酸化的调节机制，为今后治疗AD的药物设计与开发提供新思路。

阿尔茨海默病（AD）最关键的病理特征之一是tau蛋白分子在神经细胞内异常聚集。本研究采用细胞培养，RNA干扰，免疫印记，基因转染等技术，初步探讨IP6K1基因对tau蛋白异常磷酸化的影响及其机制，首次成功构建了针对人IP6K1基因的重组慢病毒干扰载体和过表达质粒，首次发现：（1）RNA干扰IP6K1基因抑制SH-SY5Y细胞的tau蛋白磷酸化，并证实可能与Akt活性增强及GSK-3β活性减弱有关；（2）RNA过表达IP6K1基因促进SH-SY5Y细胞的tau蛋白磷酸化，并证实可能与Akt活性降低及GSK-3β活性增强有关。本研究证实IP6K1是改善AD病tau蛋白异常磷酸一个可能的新靶点，有助于阐明IP6K1参与tau蛋白异常磷酸化的调节机制，为今后治疗AD的药物设计与开发提供新思路。