Disruption of Transcription Networks in Esophageal Adenocarcinoma Tumorigenesis

食管腺癌肿瘤发生中转录网络的破坏

基本信息

批准号：
10662298
负责人：
WAEL EL-RIFAI
金额：
$ 151.64万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662298
关键词：
3-Dimensional Affect Animal Model Barrett Esophagus Barrett&apos s Tumorigenesis Bile Reflux Bioinformatics Biology Biometry Cell Survival Cells Chronic Clinical Consultations Database Management Systems Development ELF3 gene Epidermal Growth Factor Receptor Esophageal Adenocarcinoma Esophagus FDA approved Frequencies Gastric Acid Gastroesophageal reflux disease Genetic Genetic Transcription Histopathology Immunohistochemistry Incidence Inflammatory Response Injury Mediating Medical Metaplasia Molecular Oncogenic Operative Surgical Procedures Organoids Outcome Oxidation-Reduction Oxidative Stress Induction PTGS2 gene Patients Pharmaceutical Preparations Play Population Preventive Principal Investigator Production Proteins Proton Pump Inhibitors Reflux Regulation Research Risk Factors Role SOX4 gene STAT3 gene Services Signal Transduction Stress Survival Rate Testing Therapeutic Therapeutic Intervention Tissue Sample Tissues Transcriptional Activation United States Western World Work adduct animal tissue bile salts cancer cell data exchange data integration efficacy evaluation experimental study human tissue in vitro Model in vivo inhibitor innovative technologies molecular pathology mouse model neoplastic cell novel novel strategies novel therapeutic intervention patient derived xenograft model pre-clinical prevent programs response therapeutic target therapy resistant tool transcription factor translational study tumor progression tumorigenesis tumorigenic

项目摘要

SUMMARY/ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades. EAC patients' 5-year survival rate is less than 15%, underscoring the need to understand the underlying biology to identify new therapeutic approaches. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts (ABS) abnormally refluxate into the esophagus, affects more than 20% of the US population. In this program project, we hypothesize that interactions between APE1 redox functions and isolevuglandins (IsoLGs) protein adducts promote activation and stability of critical oncogenic transcription networks to mediate cell survival and expansion in esophageal tumorigenesis. This program project leverages unique expertise of the principal investigators and takes advantage of advanced genetic and surgical animal models, 3-dimensional in vitro models, human tissues, patient-derived xenografts (PDXs), and innovative technologies. Project 1 investigates mechanisms by which APE1-redox function promotes activation of SOX9 transcription factor in EACs under reflux conditions. Mechanistic and functional studies will explore the role of APE1 redox function and IsoLGs adducts in regulating SOX9 to promote cancer cell survival and expansion. Translational studies will determine the efficacy APE1 redox inhibitors using in vivo mouse models. Project 2 investigates novel mechanisms of STAT3 by IsoLG protein adducts, as a cellular response to oxidative stress induced by reflux conditions. The translational experiments include the use of isoLG inhibitors to suppress formation of oncogenic protein adducts and progression to EAC in animal models of Barrett’s tumorigenesis. Project 3 investigates the role SOX4 in EAC development. The translation studies in Project 3 include testing FDA-approved drugs that inhibit SOX4, as a proof of concept to develop a novel strategy to treat EACs. The integrated data exchange in this program project will enable us to collectively investigate the role of APE1 redox functions and IsoLG protein adducts in esophageal tumorigenesis. The three proposed cores deliver key services for all the projects. The Administrative Core (Core A) will manage all scientific and fiscal issues and facilitate research interactions. The Molecular Pathology Core (CORE B) will provide histopathology and immunohistochemistry services for animal and human tissues. The Biostatistics and Bioinformatics Core (CORE C) will play a central role in providing computational, statistical, and bioinformatics services. Via these Project and Core interactions we will identify biology-relevant oncogenic molecular vulnerabilities that can be therapeutically targeted to benefit EAC patients

摘要/摘要：食管腺癌 (EAC) 的发病率增加超过过去三十年里，EAC 患者的 5 年生存率下降了六倍，这凸显了这一点。需要了解潜在的生物学以确定新的治疗方法。反流病 (GERD) 是指酸性胆汁盐 (ABS) 异常反流至食道，影响更多超过 20% 的美国人口在这个项目中，我们研究了 APE1 氧化还原之间的相互作用。功能和异黄酮素 (IsoLGs) 蛋白加合物促进关键致癌物质的激活和稳定性转录网络介导食管肿瘤发生中的细胞存活和扩张。该项目利用了主要研究人员的独特专业知识，并利用了先进的遗传和手术动物模型、3 维体外模型、人体组织、患者来源的异种移植物 (PDX) 和项目 1 研究 APE1-氧化还原功能的促进机制。回流条件下 EAC 中 SOX9 转录因子的激活机制和功能研究将进行。探讨APE1氧化还原功能和IsoLGs加合物在调节SOX9促进癌细胞存活中的作用转化研究将确定 APE1 氧化还原抑制剂在小鼠体内的功效。项目 2 通过 IsoLG 蛋白加合物研究 STAT3 作为细胞反应的新机制。转化实验包括使用 isoLG。在动物模型中抑制致癌蛋白加合物的形成和 EAC 进展的抑制剂 Barrett 的肿瘤发生研究了 SOX4 在 EAC 发育中的作用。项目 3 包括测试 FDA 批准的抑制 SOX4 的药物，作为开发新型药物的概念证明该计划项目中的综合数据交换将使我们能够共同制定治疗 EAC 的战略。研究 APE1 氧化还原功能和 IsoLG 蛋白加合物在食管肿瘤发生中的作用。拟议的三个核心为所有项目提供关键服务。行政核心（核心 A）将负责管理。所有科学和财政问题并促进研究互动。将为动物和人体组织提供组织病理学和免疫组织化学服务。生物统计学和生物信息学核心（CORE C）将在提供计算、通过这些项目和核心交互，我们将确定与生物学相关的服务。可以针对 EAC 患者进行治疗的致癌分子漏洞