Signal Transduction by PI3K/mTOR

PI3K/mTOR 的信号转导

• 批准号: 10578841
• 负责人: Jorge Silvio Gutkind
• 金额: $ 48.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578841
• 关键词: Aging; Automobile Driving; Biological Assay; Biology; Biosensor; Cell Nucleus; Cell physiology; Cells; Cellular Assay; Cessation of life; Cetuximab; Chemicals; Clinical; Color; Combined Modality Therapy; Complex; DNA Polymerase II; DNA Polymerase III; Detection; Diabetes Mellitus; Disease; Drug resistance; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Event; FDA approved; FRAP1 gene; Genetic Transcription; Goals; Location; Malignant Neoplasms; Mediating; Modeling; Molecular; Nuclear; Nuclear Translocation; Oncogenic; PIK3CG gene; Pathway interactions; Phase II Clinical Trials; Phosphotransferases; Process; Regulation; Reporter; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Technology; Testing; Toxic effect; Variant; Xenograft Model; cancer therapy; cell growth; molecular actuator; mouth squamous cell carcinoma; multiplexed imaging; nervous system disorder; novel; phosphoproteomics; recruit; response; spatiotemporal; targeted cancer therapy; tool; transcriptome sequencing; tumor; tumorigenesis

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.

项目摘要： 我们研究的总体目标是发现MTOR的分子和细胞机制 信号在空间上受到调节，并阐明亚细胞MTORC1信号对 肿瘤发生和癌症耐药性。由磷脂酰肌醇调节的信号通路3- 激酶（PI3K）和雷帕霉素（MTOR）的机理靶标会调节许多关键过程 到细胞生理，因此在包括癌症在内的疾病中常常失调。特别是持久 PI3K/MTOR信号传导电路的激活是口服最常见的失调信号机制 鳞状细胞癌（OSCC），这种疾病每年在全球造成约30万人死亡，5年 尽管具有侵略性的多模式疗法，但生存率估计约为60％。空间 PI3K/MTOR的隔室化不仅对于增强信号传导特异性至关重要，而且至关重要 正确运行路径所需的必要。但是， pi3k/mTOR信号传导仍然很了解，尚不清楚信号的哪个亚细胞池 分子有助于肿瘤发生和耐药性。我们组装了一个强大的跨学科 团队具有补充专业知识，包括化学生物学和激酶专家Jin Zhang博士 信号传导，著名的癌症生物学家J. Silvio Gutkind博士，其实验室专注于致癌 驱动OSCC启动和进展的信号通路。在我们以前的研究中，我们创造了小说 研究MTOR信号传导空间调节的工具，包括用于跟踪的荧光生物传感器 MTOR复合物1（MTORC1）活性在活细胞中的活性和一种实现亚细胞抑制的方法 激酶信号传导。使用这些工具，我们发现了核调节的基本机制 mtorc1。在OSCC的背景下，我们已经表明MTOR抑制在A中发挥有效的抗肿瘤活性 一系列遗传定义和化学诱导的OSCC模型以及A中有利的临床反应 最近完成了临床II期试验（NCT01195922）。当前的建议将发展新的分子 询问活细胞中MTORC1信号传导时空调节的工具，阐明调节 核MTORC1信号的机制，并确定亚细胞MTORC1的功能作用 OSCC中肿瘤发生和西妥昔单抗抗性的信号传导。揭示功能和调节 亚细胞MTORC1信号传导应为选择性靶向途径成分和产量提供一条路径 毒性和耐药性降低的疗法。