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Signal Transduction by PI3K/mTOR

PI3K/mTOR 的信号转导

基本信息

批准号：
10366013
负责人：
Jorge Silvio Gutkind
金额：
$ 47.86万
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/10366013
关键词：
1-Phosphatidylinositol 3-Kinase Address 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 Pathway interactions Phase II Clinical Trials Phosphotransferases Process Raptors 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 mTOR inhibition molecular actuator mouth squamous cell carcinoma multiplexed imaging nervous system disorder novel phosphoproteomics recruit response spatiotemporal targeted cancer therapy tool transcriptome sequencing 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.

项目总结: