Pilot Project 2: Nrf2 Activation in Esophageal Squamous Cell Carcinogenesis In Vivo

试点项目 2：Nrf2 激活在食管鳞状细胞体内癌变过程中的作用

基本信息

批准号：
9044453
负责人：
Michael Benjamin Major
金额：
$ 2.05万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-28 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044453
关键词：
Affect African American Biological Assay Caucasians Cell Differentiation process Cell Proliferation Chemicals Data Differentiation Antigens Disease EGFR gene EGFR inhibition Energy Metabolism Energy Metabolism Pathway Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Esophageal Esophageal Squamous Cell Esophageal Squamous Cell Carcinoma Esophagus Evaluation Event Foundations Gefitinib Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals Grant Human Hyperkeratosis Lesion Malignant Neoplasms Measures Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Monitor Mus Mutation Nuclear Oxygen Paraffin Pathway interactions Patients Phase Phenotype Phosphotransferases Pilot Projects Population Preventive Publishing Pyruvate Kinase Sampling Signal Transduction Solid Stress System Testing Tissue Sample Transcriptional Regulation Treatment Efficacy United States National Institutes of Health Western Blotting abstracting anticancer research base c-erbB-1 Proto-Oncogenes cancer health disparity carcinogenesis caucasian American clinically relevant differential expression human data in vivo inhibitor/antagonist knockout gene mouse model next generation sequencing novel nutrition outcome forecast overexpression racial disparity response targeted treatment transcription factor translational study

项目摘要

Abstract: Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans rather than Caucasian Americans at a ratio of about 4:1. African American patients with ESCC have much worse prognosis than their Caucasian counterparts. Therefore it is important to better understand molecular mechanisms of ESCC and develop targeted therapy for this deadly disease in order to reduce racial disparity. Recent NextGen sequencing studies have identified multiple driver mutations in human ESCC among which Nrf2 and Keap1 mutations are known to activate Nrf2 signaling. However, the molecular mechanisms of Nrf2-associated carcinogenesis have not been clearly understood particularly in vivo. Based on our preliminary data, we hypothesize that Nrf2 activation induces esophageal hyperproliferation and hyperkeratosis through the EGFR/PI3K/Akt pathway and metabolic reprogramming. Using the Keap1-/- mouse model of esophageal hyperproliferation and hyperkeratosis, we plan to test our hypothesis with two specific aims: (1) To examine whether Nrf2 activation in Keap1-/- esophagus activates the EGFR/PI3K/Akt pathway and metabolic reprogramming through transcriptional regulation of genes of the EGFR/PI3K/Akt pathway and energy metabolism. (2)To test whether genetic or chemical inhibition of the EGFR/PI3K/Akt pathway or metabolic reprogramming may suppress esophageal phenotype in Keap1-/- mice, and whether inhibition of both events may have synergistic effect. This Pilot Project is aimed to understand the carcinogenic mechanisms of Nrf2 activation in esophageal squamous cell carcinogenesis in vivo. If successful, it will lay down a solid foundation for translational studies on Nrf2-high ESCC and contribute to reduction of cancer health disparity in the African American population.

抽象的：食管鳞状细胞癌（ESCC）主要影响非洲裔美国人，而不是高加索人美国人的比例约为4：1。 ESCC患者的预后比他们的预后差得多高加索同行。因此，重要的是要更好地了解ESCC和ESCC的分子机制为这种致命的疾病开发针对性的治疗，以减少种族差异。最近的NextGen测序研究已经确定了人类ESCC中的多个驱动器突变，其中NRF2和KEAP1突变为已知会激活NRF2信号。但是，NRF2相关的癌变的分子机制具有特别是在体内特别理解。根据我们的初步数据，我们假设NRF2 激活通过EGFR/PI3K/AKT途径诱导食管过度增殖和高性病代谢重编程。使用食管高增殖和高胚的Keap1 - / - 小鼠模型，我们计划以两个具体目的测试我们的假设：（1）检查KEAP1中的NRF2激活是否是否激活食道激活EGFR/PI3K/AKT途径和通过转录的代谢重编程 EGFR/PI3K/AKT途径和能量代谢的基因调节。（2）测试遗传还是 EGFR/PI3K/AKT途径或代谢重编程的化学抑制可能会抑制食管 Keap1 - / - 小鼠中的表型以及对这两个事件的抑制是否可能具有协同作用。这个试点项目旨在了解食管鳞状细胞中NRF2激活的致癌机制体内致癌作用。如果成功，它将为NRF2高的翻译研究奠定坚实的基础 ESCC并有助于减少非裔美国人人口的癌症健康差异。