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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：
10247138
负责人：
Michael Benjamin Major
金额：
$ 4.67万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247138
关键词：
Affect African American Archives Biological Assay Caucasians Cell Proliferation Chemicals Data Differentiation Antigens Disease EGFR gene EGFR inhibition Energy Metabolism Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Esophageal Squamous Cell Carcinoma Esophagus Evaluation Event Foundations Gefitinib Gene Expression Genes Genetic Genetic Transcription Goals Grant Human Hyperkeratosis Lesion Malignant Neoplasms Measures Metabolic Metabolism Mitochondria Modeling Molecular Monitor Mus Mutation Nuclear Oxygen Paraffin Pathway interactions Patients Phase Phenotype Phosphotransferases Pilot Projects Population Preventive Proliferation Marker Publishing Pyruvate Kinase Quantitative Reverse Transcriptase PCR Sampling Signal Transduction Solid Stress System Testing Tissue Sample Transcriptional Regulation Treatment Efficacy United States National Institutes of Health Western Blotting anticancer research base cancer health disparity carcinogenesis carcinogenicity caucasian American clinically relevant differential expression driver mutation esophageal squamous cell carcinogenesis health disparity human data in vivo inhibitor/antagonist knockout gene metabolome 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.

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