载脂蛋白E（ApoE）在正常昼夜节律维持中的角色目前仍未阐明。初步研究显示阿尔茨海默病（AD）患者的睡眠节律紊乱与ApoE表达下调及中枢钟视交叉上核（SCN）受损有关。本项目拟通过观察ApoE基因敲除小鼠跑轮昼夜节律的紊乱情况，明确ApoE在昼夜节律维持中的作用；探讨ApoE基因敲除导致昼夜节律紊乱的机制，包括视网膜视神经节细胞黑视素（malanopsin）的表达水平和节细胞亚型分布和数量的变化，SCN神经元线粒体的变性情况、能量代谢变化、Sirt1表达异常与昼夜节律紊乱的关系，松果体褪黑素（malatonin）的分泌水平及其昼夜节律的改变，以及ApoE缺失对脑中Tau蛋白和A?蛋白表达的影响；设计出改善甚或纠正ApoE缺失后昼夜节律紊乱的措施，包括调节Sirt1的活性和改善SCN能量代谢水平等。研究结果将有助于深入认识ApoE与神经退行性病变的关系并提供防治思路和药物靶点。

The role of apolipoprotein E (ApoE) in the maintainance of circadian rhythm is still obscure. Some reports showed that patients with Alzheimer's disease (AD) frequently complained problems in sleeping, and the arrhythmic sleep-wake cycles were associated with pathological changes of retina and the central clock suprachiasmatic nucleus (SCN) and downregulation of ApoE expression. Based on these preliminary findings, the present project was designed to demonstrate the change of circadian rhythm in ApoE knockout mice by monitoring the wheel-running activities. Further, the project would explore the underlying mechanisms, including the numbers and distributions of malanopsin-expressing retinal ganglial cells and the expression level of malanopsin, the metatropy of mitochondria and energy metabolism in SCN neurons, the potential abnormalities in the expression and circadian rhythm of melatonin in the pineal gland, and the effects of ApoE deficiency on the expression of Tau and A beta proteins. Based on above studies, the project would also design some strategies for improving or even correcting the abnormal circadian rhythms in ApoE knockout mice, including regulating the activities of Sirt1 and improving the energy metabolism of the SCN. The study may help to better understand the role of ApoE in neurodegenerative diseases including AD, and provide ideas and drug targets for preventing or curing circadian rhythm disorders in subjects with ApoE deficiency.