Regulation of the JAK/STAT Signaling and Esophageal Tumorigenesis in Conditions of Esophageal Reflux Injury

食管反流损伤情况下 JAK/STAT 信号传导和食管肿瘤发生的调节

基本信息

批准号：
10662307
负责人：
ALEXANDER I. ZAIKA
金额：
$ 32.9万
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/10662307
关键词：
Affect Animal Model Animals Biochemical Biological Process Biology Cancerous Cells Chemopreventive Agent Chronic Clinical Country Data Development Digestive System Disorders Disease Duodenum Environment Esophageal Adenocarcinoma Esophagus Exposure to Gastric Acid Gastroesophageal reflux disease Genetic Genetic Transcription Health Human Incidence Inflammation Inflammatory Response Injury JAK1 gene Laboratories Lesion Link Malignant Neoplasms Metaplasia Morbidity - disease rate Oncogenic Operative Surgical Procedures Organoids PTGS2 gene Patients Precancerous Conditions Preventive Preventive treatment Process Program Research Project Grants Property Protein Inhibition Proteins Proteomics Reflux Regulation Research Risk Factors Role SOX4 gene STAT3 gene Signal Pathway Signal Transduction Signaling Protein Solid Neoplasm Specimen Stat3 protein Survival Rate Testing adduct bile salts carcinogenicity cooperative study esophageal carcinogenesis human tissue innovation insight mortality mouse model novel novel therapeutics premalignant prevent response tissue injury tool tumor tumorigenesis tumorigenic

项目摘要

ABSTRACT/ SUMMARY Esophageal adenocarcinoma (EAC) is one of the fastest rising cancers in the US. This tumor remains to be a poorly treatable disease with surgery that is the mainstay of current therapy, carrying significant morbidity and mortality. The EAC biology is tightly linked to chronic gastroesophageal reflux disease (GERD), a digestive disorder in which gastric acid and duodenal bile salts enter the esophagus causing strong tissue injury and de- velopment of Barrett’s metaplasia (BE). BE is a precancerous condition that can progress to EAC. Yet, the specific mechanisms underlying this tumorigenic process remain poorly understood limiting the development of new preventive and treatment options for EAC. We have developed an innovative hypothesis explaining how reflux induces carcinogenic alterations in the esophagus through protein adduction with reactive isolevuglandins and aberrant activation of the JAK/STAT signaling pathway. This hypothesis is supported by strong preliminary data generated by animal studies and analyses of human tissue specimens collected from patients with BE and GERD. In aim 1, we will define novel, previously uncharacterized mechanisms regulating the JAK/STAT signaling by protein adduction in conditions of esophageal reflux injury. In aim 2, we will investigate the regulation of pro- tein adducts in the esophageal niche using animal models of EAC and human clinical specimens. In aim 3, we will test various options to inhibit protein adduction in a pro-tumorigenic environment created by chronic gas- troesophageal reflux and investigate how it affects esophageal carcinogenesis. Our project is an integral part of the P01 program focused on the mechanistic studies of EAC tumorigenesis while exploring novel cancer chemopreventive and treatment options. This cooperative study will also expand and deepen our understanding of esophageal carcinogenesis by exploring the intersections of the iso- levuglandins with APE1-SOX9 and SOX4 signaling networks, examined in Projects 2 and 3. Our collective studies in this project and P01 program are expected to lay the groundwork for novel therapeutic applications.

摘要/总结食管腺癌 (EAC) 是美国发病率最快的癌症之一。一种难以通过手术治疗的疾病，手术是当前治疗的主要方法，具有显着的发病率和 EAC 生物学与慢性胃食管反流病 (GERD)（一种消化系统疾病）密切相关。胃酸和十二指肠胆汁盐进入食道造成强烈的组织损伤和脱水的疾病 Barrett 化生 (BE) 是一种癌前病变，可进展为 EAC。这种致瘤过程的具体机制仍然知之甚少，限制了肿瘤的发展预防 EAC 新生和治疗选择。我们提出了一个创新的假设，解释反流如何诱发致癌改变通过与反应性异黄酮蛋白加合和 JAK/STAT 的异常激活对食道产生影响该假设得到了动物研究和产生的强有力的初步数据的支持。对从 BE 和 GERD 患者采集的人体组织标本进行分析。在目标 1 中，我们将定义新颖的、以前未表征的调节 JAK/STAT 信号传导的机制在目标 2 中，我们将研究食管反流损伤条件下蛋白质内收的调节。在目标 3 中，我们使用 EAC 动物模型和人类临床标本研究食管生态位中的蛋白质加合物。将测试各种选项，以抑制慢性气体产生的促肿瘤环境中的蛋白质加成食管反流并研究它如何影响食管癌的发生。我们的项目是 P01 项目的一个组成部分，专注于 EAC 肿瘤发生的机制研究在探索新的癌症化学预防和治疗方案的同时，这项合作研究也将扩大。并通过探索异质性的交叉点加深我们对食管癌发生的理解 levuglandins 与 APE1-SOX9 和 SOX4 信号网络，在项目 2 和 3 中进行了检查。我们的集体该项目和 P01 计划的研究预计将为新型治疗应用奠定基础。