PI3K-mTOR signaling in stem cells, tissue homeostasis, and cancer

描述（由申请人提供）：纯化和研究正常和肿瘤干细胞的技术正在迅速发展，但我们对平衡干细胞增殖和自我更新的信号通路仍然知之甚少。PTEN/PI3K通路是干细胞维持的一个关键调控途径。PTEN是癌症中第二常发生突变的肿瘤抑制因子，在一些小鼠干细胞模型中，PTEN的删除是肿瘤启动事件。因此，了解PTEN/ pi3k依赖通路如何调节多种体细胞干细胞命运的分子基础具有广泛的意义。在本研究中，我们利用小鼠遗传学建立了间充质干细胞中PTEN/ pi3k依赖性信号通路的新模型。利用这些模型，我们将全面定义该途径控制间充质干细胞命运、组织稳态和肿瘤发展的机制。我们的研究结果将为正常和肿瘤干细胞调控的分子基础提供关键的见解。

DESCRIPTION (provided by applicant): Techniques to purify and study normal and tumor stem cells are rapidly improving, yet we still understand relatively little about the signaling pathways that balance stem cell proliferation and self-renewal. One pathway emerging as critical regulator of stem cell maintenance is the PTEN/PI3K pathway. PTEN is the second most frequently mutated tumor suppressor in cancer, and in some murine stem cell models, deleting PTEN is a tumor-initiating event. Thus, understanding the molecular basis of how PTEN/PI3K-dependent pathways regulate the fate of diverse somatic stem cells has broad implications. In this proposal, we use mouse genetics to develop novel models of PTEN/PI3K-dependent signaling pathways in mesenchymal stem cells. Using these models, we will comprehensively define the mechanism by which this pathway controls mesenchymal stem cell fate, tissue homeostasis, and tumor development. Our results will provide key insight into the molecular basis of both normal and tumor stem cell regulation.