喹唑啉类化合物GTM-1激活神经细胞自噬通路的直接作用蛋白发现与验证

阿尔兹海默氏病（Alzheimer’s disease，AD）是一种进行性发展的致死性神经退行性疾病，其主要病理特征为最终大脑中充斥着杂乱的纤维化β淀粉蛋白寡聚体。AD的病因及发病机制尚未阐明。自噬可以选择性降解异常蛋白质聚集体，对AD等神经退行性疾病具有重要的调控作用。前期我们筛选出一种新型喹唑啉类化合物GTM-1，它可以迅速诱导自噬并保护神经细胞免受β淀粉蛋白寡聚体的毒性。我们还意外的发现GTM-1不直接作用与Akt和mTOR蛋白，这与雷帕霉素（最敏感的自噬诱导剂，通过抑制Akt/mTOR/p70S6K通路来诱导自噬）不同。那么，GTM-1诱导神经细胞自噬的直接作用蛋白是什么呢？本课题拟通过亲和色谱方法寻找并验证GTM-1调节神经细胞自噬的直接作用蛋白并进行功能和结构生物学验证。本课题的完成将有助于阐明GTM-1保护神经细胞、治疗AD的分子作用机制，拓展喹唑啉衍生物在AD中的应用价值。

Alzheimer disease (AD) is a neurodegenerative disease, which eventually leads to death, and its cause and progression are not well understood. The autophagy is a selective degradation pathway. Abnormal protein aggregates, unnecessary or dysfunctional cellular components and pathogens may be selectively infiltrated into autophagosome, and are transported to lysosome for degradation. Perhaps autophagy plays a protective role in the early stage of Alzheimer disease. GTM-1, a quinazoline compound, could protect mouses' nerve by regulating the autophagy of neurons. However, it holds a different target with rapamycin. The goal of this project is to identify the potential target(s) of GTM-1 and confirm the interaction between GTM-1 and its target(s). This research will help to understand the molecular mechnism of GTM-1 and allow a better study on quinazolines' applications to the treatment of AD.