mTOR调控Notch信号在胸腺上皮细胞退化中作用机制的研究

The key problem of the thymus involution is the senescence and the function decline of thymic epithelial cells (TECs). It may cause deficiencies of T cell mediated immunity and serious damage to health. It is difficulty to reconstruct the T cell immunity for the mechanism of the TECs senescence is not clear. So it is great significance to declare mechanism of the TECs aging. The decreasing expression of Foxn1 is the characteristics of the TECs senescence. Some research work has evidenced that there were some relationship between the mTOR/Notch signaling pathways and cell senescence. mTOR control the Notch pathway in tumor development, but unfortunately the molecular mechanism is unknown. It has identified that Notch promoted the hair follicles differentiation via CSL-Wnt5a-Foxn1 pathway. In this study, we will focus on how the mTOR regulate the Fonx1 via Notch signal and contribute to the TECs senescence. It is intended to use gene knock out and transgenic animals to explore the molecular mechanism of the TECs senescence. It will be great helpful to reconstruction T cell immune for the clinic therapy of immunity deficiency caused by tumor, seriously infectious, transplantation rejection, radiotherapy and chemotherapy.

胸腺退化的关键是胸腺上皮细胞（TECs）的衰老和功能减退，可致机体T细胞免疫缺陷，严重危害个体健康，因机制不清，T细胞重建尚未成功，故研究TECs衰老机制意义重大。Foxn1表达下调是TECs衰老的重要标志。mTOR和Notch信号途径均与衰老有关。已知mTOR可调控Notch表达和活性，但分子机制不清，而Notch经CSL-Wnt5a调控Foxn1促进毛囊的分化。本项目聚焦于mTOR如何通过Notch调控Foxn1促进TECs衰老，拟利用基因敲除和转基因动物，采用细胞、分子生物学手段，揭示TECs衰老的分子机制，为临床重建T细胞免疫奠定基础。

胸腺是T细胞发育分化的重要场所，但是在出生后就开始逐渐退化，胸腺退化的关键是TECs的衰老和功能减退。可因TCR库容和T细胞输出减少，导致机体罹患肿瘤和自身免疫病。因机制不清，目前T细胞很难重建。本研究针对活化DCs可回迁胸腺，且有文献表明Jagged-1过表达胸腺细胞可诱导TECs细胞凋亡，我们建立假说：活化的DCs高表达Jagged-1回迁诱导胸腺上皮细胞衰老退化。本研究就Notch信号途径、mTOR信号途径，以及两者交互对话在TEC的衰老和退化中的作用及机制进行了一系列研究。发现活化的DCs回迁如胸腺，通过其表达的Jagged-1与TECs高表达的Notch3结合，活化Notch信号，抑制Wnt4/β-catenin，进而下调TCF活性，抑制Foxn1的表达，上调促进p21诱导TECs衰老。证明了Notch信号通过Wnt4/β-catenin/TCF-Foxn1-p21信号轴诱导TECs衰老和退化的新机制研究。同时发现Notch信号的活化，还可以激活mTORC1信号，促进p21的表达，诱导TECs的衰老与退化。Notch信号可能通过Wnt4/β-catenin与mTORC1进行交互对话调节胸腺的衰老与退化。低剂量的Jagged-1活化Notch信号促进Wnt4/β-catenin信号，但高剂量的Jagged-1引起较强的Notch活化信号抑制Wnt4/β-catenin信号。而Rapamycin抑制mTORC1可上调Wnt4/β-catenin信号，但这一机制至少部分依赖于Notch信号的活化。高度活化mTORC1可以抑制Wnt4/β-catenin信号。这一机制的阐明为将来预防TECs和胸腺萎缩提供了可能的策略，有助于预防重大疾病如新冠肺炎引起的胸腺萎缩和功能退化，具有重要意义。