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

• 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
• 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

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）是美国增长最快的癌症之一。这个肿瘤仍然是 手术治疗效果不佳的疾病，是目前治疗的主要手段，具有显著的发病率， mortality. EAC生物学与慢性胃食管反流病（GERD）密切相关，这是一种消化道疾病。 胃酸和十二指肠胆汁盐进入食管引起强烈组织损伤和脱钙的疾病， 巴雷特化生（Barrett's metaplasia，BE）BE是一种癌前疾病，可进展为EAC。然而 这种致瘤过程的具体机制仍然知之甚少，限制了 EAC的新预防和治疗选择。 我们提出了一个创新的假设，解释了反流如何诱导肿瘤细胞的致癌性改变。 食管通过与反应性异evuglandins的蛋白加合和JAK/STAT的异常激活 信号通路这一假设得到了动物研究产生的强有力的初步数据的支持， 分析从BE和GERD患者中采集的人体组织标本。 在目标1中，我们将定义新的，以前未表征的机制，调节JAK/STAT信号转导 通过蛋白加合在食管反流损伤的条件下。在目标2中，我们将研究前- 使用EAC动物模型和人类临床标本在食管龛中的蛋白加合物。在目标3中，我们 将测试各种选择，以抑制蛋白质加合在一个促肿瘤环境所创造的慢性气体- 食管反流和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，该项目专注于EAC肿瘤发生机制的研究 同时探索新的癌症化学预防和治疗选择。这项合作研究还将扩大 并通过探索食管癌发生的异基因交叉点来加深我们对食管癌发生的认识。 与APE 1-SOX 9和SOX 4信号网络，在项目2和3中检查的levuglandin。我们的集体 该项目和P01项目的研究预计将为新型治疗应用奠定基础。