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

项目总结 对NRF2高位食管瘤机制和靶向治疗资助的多样性补充 鳞状细胞癌“(R01CA244236)将扩大资助范围，研究如何提高水平 在ESCC中，活性氧物种(ROS)的活性控制着全球的激酶活性。在父母的资助中，我们是 表征食管癌中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、疗效及NRF2反应性鉴定 激酶及其在NRF2驱动的ESCC生物学中的功能。作为这项工作的补充和延伸， 提出的多样性补充填补了母项目中没有研究的一个空白--活性氧的作用 物种在ESCC中对激酶活性和信号转导的调节。这份副刊将 支持艾米丽·扎博克博士的职业发展，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。扎博克博士是分析化学和质量方面的专家。 光谱学，以及癌细胞生物学的新专业知识将增强她的学术生涯，因为她建立了 独立研究计划。在拟议的项目中，扎博克博士的目标是：1)量化ROS水平和 二维和三维培养的人鳞状细胞癌细胞系中球体的动力学2)鉴定氧化还原敏感性 ESCC中的激酶和3)决定选择的氧化还原敏感的激酶在ESCC信号转导中的作用 和细胞生物学。扎博克博士将致力于将活性氧物种与激酶联系起来，而这一过程 越来越受到重视，但尚未在ESCC模式系统中得到全面研究或审查。

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.