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）的发生率超过在过去的三十年中，六倍。 EAC患者的5年生存率小于15％，强调需要了解潜在的生物学，以识别新的治疗方法。慢性胃食管反应反流疾病（GERD），其中酸性胆汁盐（ABS）绝对反射到食道中，会影响更多超过美国人口的20％。在这个程序项目中，我们假设APE1氧化还原之间的相互作用功能和异戊瓜（Isolevuglandins）（隔离）蛋白加合物促进了关键致癌性的激活和稳定性转录网络介导食道肿瘤发生的细胞存活和扩张。这个程序项目利用主要研究人员的独特专业知识，并利用先进的遗传和手术动物模型，三维体外模型，人体组织，患者衍生的Xenographictics（PDXS）和创新技术。项目1研究APE1-REDOX功能促进的机制在反射X条件下EAC中Sox9转录因子的激活。机械和功能研究将探索APE1氧化还原函数和隔离的作用在确定SOX9促进癌细胞存活中的作用和扩展。翻译研究将使用体内小鼠确定效率APE1氧化还原抑制剂型号。项目2研究了通过Iselg蛋白加合物来研究STAT3的新机制，作为细胞反应反射X条件引起的氧化应激。翻译实验包括使用Iselg 抑制剂以抑制形成致癌蛋白加合物的形成并在动物模型中向EAC进展巴雷特的肿瘤发生。项目3调查了SOX4在EAC开发中的作用。翻译研究项目3包括测试FDA批准的抑制Sox4的药物，作为开发新颖的概念证明治疗EAC的策略。该计划项目中的集成数据交换将使我们能够集体研究APE1氧化还原函数和分离蛋白加合物在食管肿瘤发生中的作用。这三个拟议的核心为所有项目提供关键服务。行政核心（核心A）将管理所有科学和财政问题，并促进研究互动。分子病理核心（核心B）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（核心C）将在提供计算，统计和生物信息学服务。通过这些项目和核心互动，我们将确定与生物学相关的可以热靶向EAC患者的致癌分子脆弱性