SIRT1/6对细胞老化过程中生物钟改变的调控作用

项目名称： SIRT1/6对细胞老化过程中生物钟改变的调控作用

项目编号： No.31200889

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 生理学与整合生物学

项目作者： 李剑

作者单位： 泰山医学院

项目金额： 24万元

中文摘要： 生物节律随个体老化发生改变。而多种与衰老相关的机制，如胞内活性氧分子、DNA损伤、细胞周期等均受生物钟调节。沉默信息调节因子（Sirtuins）家族蛋白参与多个种属的寿命及老化过程调节,其中SIRT1对平衡CLOCK基因活性及维持生物钟节律至关重要。但关于SIRT1/6是否调控细胞老化过程中生物钟的改变报道很少。综合国内外文献和我们已有的研究结果，我们提出SIRT1/6参与调控老化过程中生物钟节律、时钟基因表达和时钟蛋白亚细胞定位改变的假说。利用外周时钟细胞衰老模型，采用荧光素酶报告基因技术、实时生物发光计数系统、染色质免疫沉降、Q-PCR等技术，系统研究细胞老化过程中时钟基因及SIRT1/6表达和功能的改变，并探讨药物阻断生物钟节律对细胞老化过程的影响。旨在阐明生物钟与老化之间相互作用及SIRT1/6调控作用，从而辅助寻找针对生物钟调节来控制老龄化相关疾病的新药靶标。

中文关键词： SITR1/6；老化；生物钟；似昼夜节律；时钟基因

英文摘要： Circadian rhythms show profound changes with ageing. On the other hand, many pathways related to ageing, such as reactive oxygen species, DNA damage response and cell cycle, are under the control of the circadian clocks. Sirtuins are a family of proteins that are involved in the ageing and longevity regulation of various species.SIRT 1 as key regulator of peripheral circadian clocks, counterbalancing the histone acetyltransferase activity of CLOCK. But little is known as for the regulatory roles of SITR1/6 in age-related circadian clock changes.Most recent studies implicated SIRT1 as a key regulator of the mammalian circadian clock. The current proposal focuses on the hypothesis that Sirtuins are involved in the modulation of age-related changes of circadian clocks in cells. Using young and senescent cells as models of peripheral clocks, we will systematically investigate changes in clock gene expression/localization, circadian rhythmicity and expression/activity changes in SIRT1/6 during cellular ageing. We will also study the impacts of clock disruptions on the susceptibility to cellular senescence, as well as the effects of manipulating SIRT1/6 activities. Key techniques include luciferase reporter assay, real-time bioluminescence imaging, ChIP, Q-PCR, Western blotting and Immunofluorescence. This study aim

英文关键词： SITR1/6；aging；biological clock；circadian rhythm；clock gene