端粒如何影响非分裂细胞衰老是一备受争议的论题。我们发现端粒存在端粒外作用，参与非再生组织衰老的新机制。前期研究证明端粒蛋白TRF2结合间质性端粒，发挥端粒外作用：转录调控神经特异蛋白PPP2R2C表达，去磷酸化修饰DNA损伤蛋白，延缓细胞衰老。本课题以神经组织为对象，探索端粒外作用参与非再生组织衰老的机制：⑴用表达Aβ的细胞和阿尔兹海默病小鼠模型，体内外研究TRF2调控PPP2R2C能改善神经细胞对DNA损伤的敏感性；⑵构建表达Tau蛋白的模型，研究TRF2调控PPP2R2C磷酸酶活性，清除异常蛋白堆积，延缓神经细胞衰老；⑶用神经干细胞和基因敲除斑马鱼模型，研究TRF2和PPP2R2C在干细胞功能和组织修复的作用。本项目将阐明端粒体系在非再生器官存在端粒外非经典通路，配合复制衰老的经典通路，延长细胞寿命，促进干细胞功能和组织修复。这是端粒调控衰老的新机制，为预防和治疗退行性疾病提供新思路。

How telomeric components are implicated in the cellular senescence of non-dividing cells are not clear. We have found that telomeres have extra-telomeric effect and it might be responsible for the ageing of non-generative tissues. Our previous results showed that telomere replicative protein 2 (TRF2) binds to interstitial telomereic sequence (ITS) and exhibits extra-telomeric effect, including transcriptional regulation of the expression of neural specific protein PPP2R2C, dephosphorylation modification of DNA damage proteins and elongation of cellular life. In this project,we will study how the extra-telomeric effect is involved in the ageing of non-generative organs based on neural tissues: 1)in-vivo and in-vitro study whether TRF2 relieves DNA damage effect on neural cells through transcriptional regulation of PPP2R2C with the cell model expressing Aβ and Alzheimer's mouse model;2) we will establish a neural cell model expressing Tau, then study how TRF2 regulates phosphatase through regulating PPP2R2C, which will remove the deposition of abnormal proteins, for example p-Tau and extend cell longivity;3) we will focus on the role of TRF2 and PPP2R2C in the stemness and tissue repair. This project will elucidate whether telomeric components contain an extra-telomeric function which is a non-canonical signaling pathway in the protection against the degeneration of non-generative tissues,like neural tissues and faciliating tissue repair. In general, this project will contribute to the screening of senescence markers, prevention of organ fibrosis and the treatment of degenerative diseases.