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: 10407746
• 负责人: ALEXANDER I. ZAIKA
• 金额: $ 34.91万
• 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/10407746
• 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; Lead; Lesion; Link; Malignant Neoplasms; Metaplasia; Morbidity - disease rate; Oncogenic; Operative Surgical Procedures; Organoids; PTGS2 gene; Patients; Precancerous Conditions; Preventive treatment; Process; Program Research Project Grants; Property; 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; base; 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/摘要 食管腺癌（EAC）是美国最快的癌症之一。这个肿瘤仍然是 通过手术治疗不佳的疾病，这是当前疗法的中流疾病，具有明显的发病率和 死亡。 EAC生物学与慢性胃食管反射疾病（GERD）紧密相关，该疾病是一种消化系统 胃酸和十二指肠胆汁盐进入食道的疾病，导致强大的组织损伤和DE- Barrett Metaplasia（BE）的速度。 BE是一种可以发展为EAC的癌前状况。但是， 这种肿瘤过程的基本特定机制仍然很糟糕地限制了限制的发展 EAC的新预防和治疗选择。 我们开发了一种创新的假设，解释了如何反映了 通过蛋白质添加蛋白质与反应性异甲素蛋白和JAK/STAT的异常激活通过食道 信号通路。该假设得到了动物研究产生的强大初步数据的支持 从BE和GERD患者收集的人体组织标本的分析。 在AIM 1中，我们将定义调节JAK/STAT信号的小说，以前未表征的机制 通过食管反射损伤的条件下的蛋白质添加。在AIM 2中，我们将调查主管的调节 使用EAC和人类临床标本的动物模型，食管生态位中的Tein加合物。在AIM 3中，我们 将测试各种选择以抑制慢性气体创造的氧化型环境中添加蛋白质的添加 Troesophapeal Replux并研究它如何影响食道癌。 我们的项目是P01计划不可或缺的一部分，该计划的重点是EAC肿瘤发生的机械研究 同时探索新​​型的癌症化学预防和治疗选择。这项合作研究也将扩大 并通过探索ISO-的相互作用来加深我们对食道癌发生的理解 带有APE1-SOX9和SOX4信号网络的Levuglandins，在项目2和3中进行了检查。我们的集体 预计该项目和P01计划的研究将为新的治疗应用奠定基础。