Signal Transduction by PI3K/mTOR

项目总结： 我们研究的总体目标是揭示mTOR的分子和细胞机制 信号是空间调节的，并阐明亚细胞mTORC1信号对 肿瘤发生与癌症治疗耐药。磷脂酰肌醇3-调节的信号通路 蛋白激酶(PI3K)和雷帕霉素的机械靶点(MTOR)调节着许多关键的过程 对细胞生理学有影响，因此在包括癌症在内的疾病中常常处于失调状态。尤其是，坚持不懈 PI3K/mTOR信号通路的激活是口腔中最常见的失调信号机制 鳞状细胞癌(OSCC)是一种每年在全球范围内导致约30万人死亡的疾病， 尽管进行了积极的多模式治疗，估计存活率约为60%。空间 PI3K/mTOR的区段划分不仅是提高信号特异性的关键，而且也是提高信号转导特异性的关键 这是该途径正常运作所必需的。然而，潜在的空间调控机制 PI3K/mTOR信号仍然知之甚少，也不清楚哪些亚细胞池的信号 分子有助于肿瘤的发生和治疗耐药。我们已经组建了一支强大的跨学科 具有互补专业知识的团队，包括化学生物学和激酶专家张进博士 J·西尔维奥·古特金德博士是一位著名的癌症生物学家，他的实验室专注于致癌基因的研究 推动口腔鳞状细胞癌启动和进展的信号通路。在我们之前的研究中，我们创造了小说 研究mTOR信号空间调控的工具，包括用于跟踪的荧光生物传感器 MTOR复合体1在活细胞中的活性及其实现亚细胞抑制的途径 激活素信号。使用这些工具，我们发现了核调控的新机制 MTORC1.在口腔鳞状细胞癌的背景下，我们已经证明mTOR抑制在 大系列基因定义和化学诱导的口腔鳞状细胞癌模型和良好的临床反应 最近完成的临床II期试验(NCT01195922)。目前的提议将开发新的分子 在活细胞中询问mTORC1信号的时空调控的工具，阐明调控 核内mTORC1信号转导机制及亚细胞mTORC1的功能作用 口腔鳞癌中肿瘤发生和西妥昔单抗耐药的信号转导。解构网络技术的功能与调控 亚细胞mTORC1信号应该提供一条选择性靶向通路成分和产量的途径 毒性和耐药性降低的治疗方法。

Project summary: The overall goal of our research is to uncover the molecular and cellular mechanisms by which mTOR signaling is spatially regulated and to elucidate the contribution of subcellular mTORC1 signaling to tumorigenesis and cancer therapy resistance. The signaling pathway regulated by phosphatidylinositol 3- kinase (PI3K) and mechanistic target of rapamycin (mTOR) regulates a number of processes that are critical to cell physiology, and therefore is often dysregulated in diseases, including cancer. In particular, persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in oral squamous cell carcinoma (OSCC), a disease that results in ~300,000 deaths each year worldwide, with 5-year survival estimates of approximately 60%, despite aggressive multimodality therapies. Spatial compartmentalization of PI3K/mTOR is not only critical for enhancing the signaling specificity, but also required for proper functioning of the pathway. However, the mechanisms underlying spatial regulation of PI3K/mTOR signaling remain poorly understood and it is not clear which subcellular pools of the signaling molecules contribute to tumorigenesis and therapy resistance. We have assembled a strong interdisciplinary team with complementary expertise, including Dr. Jin Zhang, an expert in chemical biology and kinase signaling, Dr. J. Silvio Gutkind, a renowned cancer biologist whose lab has focused on the study of oncogenic signaling pathways driving OSCC initiation and progression. In our previous studies, we have created novel tools for studying the spatial regulation of mTOR signaling, including a fluorescent biosensor for tracking mTOR Complex 1 (mTORC1) activity in living cells and an approach for achieving subcellular inhibition of kinase signaling. Using these tools, we discovered novel mechanisms underlying regulation of nuclear mTORC1. In the context of OSCC, we have shown that mTOR inhibition exerts potent antitumor activity in a large series of genetically-defined and chemically-induced OSCC models and favorable clinical responses in a recently completed clinical phase II trial (NCT01195922). The current proposal will develop new molecular tools to interrogate the spatiotemporal regulation of mTORC1 signaling in living cells, elucidate the regulatory mechanisms of nuclear mTORC1 signaling, and determine the functional roles of subcellular mTORC1 signaling in tumorigenesis and Cetuximab resistance in OSCC. Unravelling the function and regulation of subcellular mTORC1 signaling should offer a path toward selective targeting of pathway components and yield therapies with reduced toxicity and resistance.