Common epigenetic pathways regulating ageing and circadian clocks: implications for therapeutic intervention

变老的一个重要特征是睡眠质量变差。睡眠是由生物钟调节的，生物钟是身体各个器官的内部时间片段，由生物钟基因和蛋白质组成，能够产生24小时的节律输出。与年龄相关的睡眠障碍被认为是由于失去适当的昼夜节律调节，如振幅降低，非24小时周期性或不适当的阶段。从长远来看，研究生物钟随年龄增长的变化将有助于设计针对老年人睡眠障碍的治疗药物。时钟基因和蛋白质的表达和稳定性由诸如乙酰化/去乙酰化等修饰控制，描述目标蛋白上乙酰基的存在或不存在。许多这些修饰机制被发现是衰老的标志。我将使用动物模型和从人类受试者活检中分离的皮肤细胞来研究衰老过程中节律和乙酰化/去乙酰化活动的变化。修饰的改变将与昼夜节律的改变相关。通过填写问卷，将生物钟和睡眠模式与皮肤细胞的节律联系起来。我还将探讨通过药物改变乙酰化/去乙酰化平衡的可能性，以恢复与年龄相关的节律变化。

One important feature of getting old is deteriorated sleep quality. Sleep is regulated by circadian clocks, the internal time pieces in various body organs, consisting of clock genes and proteins that are capable of generating ~24 hr rhythmic outputs. Age-associated sleep disorders are thought to be due to loss of proper circadian regulation, such as reduced amplitude, non-24 hour periodicity or inappropriate phase. Studying changes in circadian clocks with ageing will in the long run aid therapeutic drug design targeting sleep disorders in the elderly.Expression and stability of the clock genes and proteins are controlled by modifications such as acetylation/deacetylation, describing the presence or absence of the acetyl group on target proteins. Many of these modification mechanisms have been found as hallmarks for ageing. I will investigate changes of rhythms and acetylation/deacetylation activities with ageing process using animal models and skin cells isolated from biopsies of human subjects. Changes of modifications will be correlated with alterations in circadian rhythms. By filling in questionnaire, the chronotype and sleep pattern will be correlated to the rhythms in skin cells. I will also probe the possibility of altering the acetylation/deacetylation balance by drugs in order to restore the age-related rhythm changes.