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Mechanisms and Targeted Therapy of NRF2-high Esophageal Squamous Cell Carcinoma

NRF2高食管鳞癌的机制及靶向治疗

基本信息

批准号：
10530998
负责人：
XIAOXIN Luke CHEN
金额：
$ 8.34万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530998
关键词：
3-Dimensional Affect Anabolism Analytical Chemistry Apoptosis Architecture Automobile Driving Biochemistry Biological Models Biology CDKN2A gene CUL3 gene Cancer Etiology Cell Line Cells Cellular biology Cessation of life Complement Data Data Set Development Plans Diagnosis Drug Metabolic Detoxication Drug Screening Epithelial Epithelial Cells Esophageal Squamous Cell Carcinoma Esophagus Event Experimental Models Expression Profiling Funding Funding Mechanisms Gatekeeping Genes Genetic Genetic Transcription Grant Growth Human Human Cell Line Hyperactivity Hyperplasia In Vitro Lesion LoxP-flanked allele Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Metabolism Modeling Molecular Molecular Biology Mus Mutate Mutation Neoplasm Metastasis Normal Cell Oncogenic Organoids Oxidation-Reduction PI3K/AKT PIK3CA gene Parents Pathway interactions Patients Pharmacology Pharmacology Study Phase Phenotype Phosphotransferases Preventive Proteomics Pyruvate Kinase Reactive Oxygen Species Recurrence Regulation Reporting Research Role Signal Pathway Signal Transduction Stress Surveys Survival Rate TP53 gene Testing Therapeutic Tissue Microarray Tissues Tumor Promoters United States Validation Work Xenograft procedure advanced disease cancer cell cancer type career career development differential expression experimental study genomic locus in vivo inhibitor member metabolomics molecular phenotype multiple omics novel novel therapeutics parent grant parent project programs response skills small molecule small molecule inhibitor targeted treatment transcription factor transcriptome sequencing tumor progression

项目摘要

PROJECT SUMMARY This diversity supplement to the funded “Mechanisms and Targeted Therapy of NRF2high Esophageal Squamous Cell Carcinoma” (R01CA244236) will expand the scope of the funded grant to study how levels of reactive oxygen species (ROS) governs global kinase activity in ESCC. In the parent grant, we are characterizing the molecular and phenotypic consequences of NRF2 hyperactivation in ESCC, determining the mechanisms of action and efficacy of NRF2 small molecule inhibitors, and identifying NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. As a complement and extension of this work, the proposed diversity supplement fills a void not studied in the parent project—the role of reactive oxygen species in the regulation of kinase activity and kinase signal transduction in ESCC. This supplement will support Dr. Emily Zarbock’s career development, giving her new scientific skills in cancer cell biology, molecular biology and signal transduction. Dr. Zarbock is an expert in analytical chemistry and mass spectrometry, and new expertise in cancer cell biology will enhance her academic career as she builds her independent research program. In the proposed project, Dr. Zarbock aims to: 1) quantify ROS levels and dynamics in ESCC human cell lines grown in 2D and in 3D as spheroids 2) identify Redox-sensitive kinases in ESCC and 3) determine the role of select redox-sensitive kinases on ESCC signal transduction and cell biology. Dr. Zarbock will work to connect reactive oxygen species to kinases, which while being increasingly appreciated, has not been comprehensively studied or examined in ESCC model systems.

项目概要这是对资助的“NRF2high 食管癌的机制和靶向治疗”的多样性补充鳞状细胞癌”（R01CA244236）将扩大资助范围，以研究鳞状细胞癌的水平如何活性氧 (ROS) 控制食管鳞癌中的整体激酶活性。在家长补助金中，我们表征 ESCC 中 NRF2 过度激活的分子和表型后果，确定 NRF2 小分子抑制剂的作用机制和功效，并识别 NRF2 反应性 NRF2 驱动的 ESCC 生物学中的激酶及其功能。作为这项工作的补充和延伸，拟议的多样性补充填补了母项目中未研究的空白——活性氧的作用 ESCC 中激酶活性和激酶信号转导的调节物种。本补充将支持 Emily Zarbock 博士的职业发展，赋予她在癌细胞生物学方面的新科学技能，分子生物学和信号转导。 Zarbock 博士是分析化学和质量方面的专家光谱测定法和癌细胞生物学方面的新专业知识将在她建立自己的学术生涯的过程中增强她的学术生涯。独立研究计划。在拟议的项目中，Zarbock 博士的目标是：1) 量化 ROS 水平并在 2D 和 3D 球体中生长的 ESCC 人类细胞系的动力学 2) 识别氧化还原敏感 ESCC 中的激酶以及 3) 确定选择的氧化还原敏感激酶对 ESCC 信号转导的作用和细胞生物学。扎博克博士将致力于将活性氧与激酶连接起来，同时越来越受到重视，但尚未在 ESCC 模型系统中进行全面研究或检查。