Signal Transduction by PI3K/mTOR

PI3K/mTOR 的信号转导

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：我们研究的总体目标是揭示 mTOR 的分子和细胞机制信号传导受到空间调节，并阐明亚细胞 mTORC1 信号传导对肿瘤发生和癌症治疗耐药性。磷脂酰肌醇3-调节的信号通路激酶 (PI3K) 和雷帕霉素的机制靶标 (mTOR) 调节许多至关重要的过程细胞生理学，因此在包括癌症在内的疾病中经常失调。尤其是坚持不懈的 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) 是一种每年导致全球约 300,000 人死亡的疾病，五年内死亡尽管采取了积极的多学科治疗，但预计生存率仍约为 60%。空间 PI3K/mTOR 的区室化不仅对于增强信号传导特异性至关重要，而且通路正常运作所必需的。然而，空间调控的机制 PI3K/mTOR 信号传导仍然知之甚少，也不清楚该信号传导的哪些亚细胞池分子有助于肿瘤发生和治疗耐药。我们组建了强大的跨学科团队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. Silvio Gutkind 博士是一位著名的癌症生物学家，他的实验室专注于致癌物质的研究驱动 OSCC 发生和进展的信号通路。在我们之前的研究中，我们创造了新颖的研究 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活细胞中 mTOR 复合物 1 (mTORC1) 的活性以及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新机制 mTORC1。在 OSCC 的背景下，我们已经证明 mTOR 抑制在多种细胞中发挥有效的抗肿瘤活性大量基因定义和化学诱导的 OSCC 模型以及良好的临床反应最近完成了临床II期试验（NCT01195922）。目前的提案将开发新的分子探究活细胞中 mTORC1 信号传导的时空调节的工具，阐明调节核 mTORC1 信号传导机制，并确定亚细胞 mTORC1 的功能作用 OSCC 中肿瘤发生和西妥昔单抗耐药性中的信号传导。揭示其功能和调节亚细胞 mTORC1 信号传导应提供一条选择性靶向途径成分和产量的途径具有降低毒性和耐药性的疗法。