大脑衰老过程中组蛋白修饰对神经干细胞稳态的调控作用及其机制研究

The aged brain has an enhanced susceptibility to neurodegenerative diseases. To date, the problem of low efficacy of available therapies for the aged brain and the neurodegenerative diseases remains largely unsolved. The maintenance of homeostasis of neural stem cells features the neural regeneration ability and plays an important role in the anti-ageing of brain. Our research group found that the neural stem cell homeostasis was impaired during the brain ageing. The growth activity of neural stem cells from the elder significantly declined compared to the young. We also found that the epigenetic drug that changed histone modifications could regulate the homeostasis of neural stem cells from the elder. Our data suggest that the histone modifications might be able to influence the brain ageing process through regulating neural stem cell homeostasis, and might be the potential drug targets for anti-ageing medicine. Based on our previous research, in the research project of our grant proposal we will further investigate the dynamic changes of histone modifications during brain ageing to find out the age-associated histone modification marks. We will study the functions of the histone modification marks in the maintenance of homeostasis of neural stem cells. Moreover, we will study the regulatory mechanisms of these functional histone modification marks with the transcriptome sequencing technology. We anticipate that our research will uncover the mechanisms of histone modification marks as the molecular signals and the anti-ageing targets in the aged brain. We hope to provide insightful understanding of histone modulators as novel therapies in the anti-ageing medicine for the brain and in the treatments of neurodegenerative diseases.

大脑衰老容易引发神经退行性疾病，目前尚无延缓大脑衰老和治疗神经退行性疾病的有效方法。神经干细胞稳态的维持不仅是神经再生能力的表现，而且对延缓大脑衰老起重要作用。本项目组发现大脑衰老过程中神经干细胞稳态会发生改变，老年神经干细胞的生长活力明显降低，并发现表观遗传药物介导的组蛋白修饰变化调控了老年神经干细胞的稳态，这表明组蛋白修饰通过调控神经干细胞稳态影响大脑衰老的进程，是潜在的抗衰老靶点。本项目拟在以上研究基础上，继续深入研究组蛋白修饰在大脑衰老过程中的变化情况，寻找与衰老相关的组蛋白修饰位点，研究这些组蛋白修饰位点在神经干细胞稳态维持中的功能，并结合转录组测序技术分析这些具有功能性的组蛋白修饰位点的分子调控机制，探索以组蛋白修饰位点作为大脑衰老的分子信号和延缓衰老的潜在药物靶点的机理，以期为临床上寻找延缓大脑衰老的新途径和治疗神经退行性疾病的新方法提供重要的理论依据。

为了揭示大脑衰老过程中干细胞命运受到的调控及其表观遗传的分子机制，本项目首先改进了用于分析干细胞功能的流式细胞检测技术，分析了干细胞再生能力减退的表型，申请了国家级专利一项且已获得专利公布。其次，成功建立了研究大脑干细胞组蛋白修饰调控机制的技术平台，研究了组蛋白H3K9甲基化修饰识别因子Cbx3及其蛋白质复合体调控神经干细胞命运的机制，并且在国际学术期刊发表了论文《Cbx3 Maintains Lineage Specificity During Neural Differentiation》。进一步利用该技术平台研究了神经干细胞衰老过程中的组蛋白甲基化修饰的差异位点和差异基因的功能。最后，探索了细胞外基质对干细胞命运的调控机制，并在国际学术期刊发表论文《Composition and Mechanism of Three-Dimensional Hydrogel System in Regulating Stem Cell Fate》。