【作者】 孟艳；

【导师】 赵春华； 张宏冰；

【作者基本信息】 中国协和医科大学 ， 内科学， 2008， 博士

【摘要】 PI3K-Akt-mTOR信号通路在生物体内众多细胞信号通路中占据相当重要的地位,参与调控如增殖、代谢、生长、分化、凋亡等多种生命现象,同时在炎症、肿瘤、代谢和心血管疾病的发病机制中起重要作用,对PI3K-Akt-mTOR通路的研究是目前生命科学研究领域的热点。本文的第一部分探讨mTOR信号通路与细胞分化之间的关系。细胞分化的异常可以引起多种疾病,肿瘤就是一种分化异常的疾病。而PI3K-Akt-mTOR通路涉及多个原癌基因和抑癌基因,该通路的异常活化在肿瘤中最为常见。实验结果表明,mTOR信号通路的过度活化对细胞分化起着阻碍的作用。同时研究结果表明,mTOR信号通路对于分化的影响是通过对Notch信号通路的调控来实现的。该调控过程涉及多个分子的参与,形成了mTOR—p63—Jagged-1—Notch的通路对分化进行调控。此项研究对于探讨肿瘤发生机制和治疗都有着重要的作用。本文的第二部分主要研究PI3K-Akt-mTOR信号通路对胰岛素信号通路的调控机制。实验结果表明,PI3K-Akt-mTOR信号通路中的重要受体PDGFR对胰岛素信号通路起着重要的调控作用。PDGFR对胰岛素信号通路的调控是通过对胰岛素通路下游分子胰岛素受体底物(insulin receptor substrates,IRS)的调控来实现的。本文的第三部分旨在比较PI3K-Akt-mTOR信号通路在间充质干细胞(Mesenchymal stem cells,MSCs)和脂肪前体细胞系3T3-L1的成脂肪分化过程中的作用。实验结果表明,在3T3-L1成脂肪分化过程中需要mTOR信号通路的激活,而且这个过程需要胰岛素的参与。而在MSCs的成脂肪分化过程中,mTOR信号通路却呈现下调趋势。因此,mTOR信号通路在这两种前体细胞中的作用是不同的,这是由上述两种细胞的本质和在生物体内所起的作用不同所决定的。更多还原

【Abstract】 PI3K-Akt-mTOR signal pathway plays various roles in cell metabolism, proliferation, apoptosis, growth and differentiation. Malfunction of this pathway has been implicated in human cancer, inflammation, metabolism, and cardiovascular disease. Therefore, this pathway is regarded as one of the most important signaling pathways and is currently under intensive investigation.Aberrant cell differentiation can result in many disorders, such as cancer. Cancer is a differentiation defective disease. In the first part of this thesis, we investigated the relationship between mTOR signal pathway and cell differentiation. Multiple proto-oncogenes and tumor-suppressor genes in PI3K-Akt-mTOR signal pathway are frequently altered in tumors. Our experimental results show that over-activation of mTOR signal pathway suppresses cell differentiation, which is Notch dependent and through p63—Jagged-1—Notch cascade. Our findings may gain some insights into the mechanism of tumorigenesis and provide novel approaches for cancer therapy.In the second part of this thesis, we demonstrated that PDGFR, an important RTK in PI3K-Akt-mTOR signal pathway, contributes significantly to the regulation of insulin signaling through regulating IRS (insulin receptor substrates) which is pivot in the downstream of insulin pathway.In the third part of this thesis, we studied the effects of the activity of PI3K-Akt-mTOR signal pathway on the differentiation of MSCs (Mesenchymal stem cells) and murine 3T3-L1 preadiocyte cell line. The activation of mTOR signal pathway is required for the differentiation of murine 3T3-L1 preadiocyte cell line which is insulin-dependant. On the contrary, mTOR signal pathway is down-regulated during the differentiation of MSCs.更多还原