Understanding circadian clock genes in ageing and cognition

该项目的总体目标是确定昼夜节律如何随年龄变化的分子基础，并最终确定是否可以确定将健康的昼夜节律延长到老年的生物机制。在细胞水平上，自我维持的昼夜节律的产生是通过“时钟基因”产生的，如周期(PER)、时钟(CLK)、隐色素(Cry)和脑肌肉Arnt-like 1(BMal1)。涉及这些基因的一系列互锁转录/翻译反馈环产生并维持这些节奏。对转基因小鼠的研究表明，时钟基因与衰老之间存在关联。我们已经在小鼠中发现了随着年龄的增长而出现的异常昼夜活动。我们还在阿尔茨海默病转基因小鼠模型中发现了类似的运动活动昼夜节律异常，并伴随着昼夜节律基因如PER和Cry在大脑中表达的变化。有许多问题需要研究，例如时钟基因的表达是如何随着年龄的变化而变化的？行为模式是否与时钟基因表达减少有关？年龄是否会影响记忆力等其他行为的节奏？阅读：Banks等人，2017哺乳动物基因组27：332-340。Oyegbami等人，2017当代阿尔茨海默病研究8：850-860。

The overall aim of this project is to identify the molecular basis of how circadian rhythms alter with age and ultimately whether a biological mechanism can be identified to prolong healthy circadian rhythms into old age. At the cellular level the generation of self-sustained circadian rhythms is produced via "clock genes" such as Period (Per), Clock (Clk), Cryptochrome (Cry) and Brain muscle ARNT-like1 (Bmal1). A series of Interlocking transcriptional/translational feedback loops involving these genes generate and sustain these rhythms. An association between clock genes and ageing has been suggested by studies in genetically modified mice. We have identified abnormal circadian activity with increasing age in mice. We have also found similar abnormality in circadian rhythms in locomotor activity accompanied by altered expression in brain of circadian genes such as Per and Cry in a transgenic mouse model for Alzheimer's disease. There many questions to be investigated, for example how is clock gene expression altered with age? Are the behavioural patterns associated with reduced clock gene expression ? does age affect the rhythm of other behaviours such as memory ? Reading : Banks et al., 2017 Mammalian genome 27: 332-340. Oyegbami et al, 2017 Current Alzheimer Research 8 : 850-860.