端粒和mTOR信号通路对小肠干细胞衰老的作用机理

Telomere is related to aging and aging associated diseases,such as intestinal dysfunction. Adult stem cell aging is related to organismal aging and dysfunction. It is known that telomere dysfunction can induce the intestinal stem cell aging and and associated dysfunction in stem cell differentiation,regeneration and maintenance. Mammalian target of rapamycin (mTOR)is shown to correlated to intestinal stem cell (ISC) aging and maintenance. However, the real mechanism of how the mTOR regulating the ISC aging in response to telomere dysfunction is unclear.We use mouse model to study the role of mTOR signalling pathway in regulating the ISC aging in response to telomere dysfunction, in which the activity of mTOR was activaed or restricted. we will also use the different age of human small intestinal specimen to study the number of ISC and the gene expression related to the mTOR signalling pathway,thus to provide the experimantal evidence for targeting retarding the aging.

端粒与人类衰老和衰老相关性疾病有关，包括小肠功能障碍。成体干细胞的衰老与组织器官的衰老及功能障碍密切相关。目前已知端粒功能障碍可以引起小肠干细胞（ISC）的衰老及功能障碍，包括小肠干细胞的分化、自我更新能力及稳态的维持。雷帕霉素靶蛋白（mTOR）信号通路参与小肠干细胞（ISC）的稳态维持和再生。在端粒功能障碍（telomere dysfunction）引起小肠功能障碍的过程中，mTOR信号通路如何调节小肠干细胞的稳态还不清楚。本项目围绕端粒与ISC衰老，以mTOR信号通路为切入点，利用基因敲除小鼠模型和化学方法，上调或抑制mTOR信号通路的活性，揭示mTOR在端粒功能障碍引起ISC衰老及功能障碍的分子调控机制。并进一步在临床病例中验证，探索规律，阐明mTOR信号通路在小肠干细胞衰老及功能障碍中的作用。为靶向调控小肠干细胞的衰老提供实验证据。

本课题围绕端粒、衰老、mTOR 以及炎症肿瘤等开展研究，利用调控mTor 的信号通路研究端粒功能障碍小鼠中小肠干细胞衰老，以及小肠干细胞所在的niche潘氏细胞的变化，同时研究了端粒以及端粒缺陷和DNA损伤相关蛋白在肠道肿瘤中的作用及机制。研究发现下调mTOR信号通路增加了小肠干细胞的数量以及潘氏细胞的数量，但是没有改变小肠干细胞的功能。发现了端粒与肠道肿瘤密切相关，端粒越短肿瘤分期越晚，而且与肿瘤的预后密切先关即端粒越短预后越差。发现了端粒缺陷和DNA损伤相关蛋白可以预测大肠癌肝转移的发生并且与肠癌预后密切相关，提示该蛋白可以作为预测肠癌肝转移的有力标志物，提高该蛋白促进了结肠癌细胞的迁移能力。这些结果为进一步转化到临床应用提供了实验依据。