Regulation of gastroesophageal reflux-associated tumorigenesis

胃食管反流相关肿瘤发生的调节

• 批准号: 8732012
• 负责人: ALEXANDER I. ZAIKA
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732012
• 关键词: Acids; Affect; Animal Model; Animal Testing; Animals; Bile Acids; Biopsy; Cancerous; Cell Culture Techniques; Cells; Chemopreventive Agent; Chronic; Clinical; Complement; DNA Damage; DNA Repair; Data; Development; Diagnosis; Disease; Disease model; Dominant-Negative Mutation; Enzymes; Epithelial; Esophageal; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophageal Tissue; Esophagus; Exposure to; Family; Gastric Acid; Gastric Juice; Gastroesophageal reflux disease; Genes; Genetic Transcription; Genomics; Genotoxic Stress; Health; Human; In Vitro; Incidence; Inflammation; Injury; Intestines; Knowledge; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Metaplasia; Metaplastic; Mus; Pathology; Patients; Play; Population; Premalignant; Prevention; Preventive; Protein Family; Protein Isoforms; Protein p53; Reflux; Regulation; Risk; Risk Factors; Rodent Model; Role; Stomach; Testing; Therapeutic; Tissues; Translations; Tumor Suppressor Proteins; Veterans; abstracting; base; bile salts; clinically relevant; cost effective; design; human tissue; improved; in vivo; innovation; insight; member; mouse model; neoplastic; novel; protein p73; response; screening; standard of care; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Esophageal adenocarcinoma (EA) is a serious clinical problem due to its high and rapidly increasing incidence rate, and the limited treatment options currently available. This disease has now overtaken other histological types of esophageal tumors in the US. The major risk factor for EA is gastroesophageal reflux disease (GERD), which affects 10 to 20% of the US population. Under conditions of GERD, esophageal cells are ex- posed to acidic gastric juice frequently mixed with duodenal bile acids. The reflux exposure causes chronic inflammation, and excessive tissue and DNA damage, resulting in the accumulation of tumorigenic alterations and progression to EA through Barrett's metaplasia (BE). However, the majority of GERD and BE patients re- cover without malignant transformation, with only a fraction going on to develop an esophageal tumor. It is therefore important to uncover mechanisms that underlie tumor progression, to enable both the identification of targets for screening at risk patients and the development of new preventive therapies for esophageal tumors. We have developed an innovative hypothesis to investigate specific mechanisms of DNA damage repair in conditions of esophageal reflux injury and to apply this knowledge to design novel chemopreventive therapies. This hypothesis is supported by strong preliminary data from human tissues, animal models, and extensive in vitro studies. We have demonstrated that the p73 protein plays a critical role in esophageal tumorigenesis and regulation of DNA damage repair under conditions of esophageal reflux injury caused by GERD. We have also identified a new group of chemopreventive compounds that can specifically activate the protective function of p73 and decrease DNA damage caused by reflux. We will build on these findings to further investigate the role played by p73 and other members of the p53 protein family in the progression to esophageal adenocarcinoma. In aim 1, we will dissect the mechanisms of DNA damage repair regulated by p73 under conditions of esophageal reflux. In aim 2, we will investigate esophageal tumorigenesis in vivo. We will employ gastroesophageal reflux injury mouse models and esophageal organotypic cultures to recapitulate human GERD-associated pathology and dissect the mechanisms of DNA damage repair. These studies will be complemented with analyses of human esophageal precancerous and cancerous lesions. In aim 3, we will explore the chemopreventive potential of compounds that induce the p73 protective activity under conditions of GERD. Our findings will have a strong impact on the understanding of multistep tumorigenesis associated with GERD and BE. Importantly, our results could help to reveal potential risk factors for esophageal tumor development and lay the groundwork for development of novel chemopreventive approaches in at risk patients with GERD and BE.

描述（由申请人提供）： 项目摘要/摘要食管腺癌 (EA) 是一个严重的临床问题，因为其发病率高且迅速增加，而且目前可用的治疗选择有限。在美国，这种疾病现已超过其他组织学类型的食管肿瘤。 EA 的主要危险因素是胃食管反流病 (GERD)，该病影响 10% 至 20% 的美国人口。在胃食管反流病的情况下，食管细胞暴露于经常与十二指肠胆汁酸混合的酸性胃液中。反流暴露会导致慢性炎症以及过度的组织和 DNA 损伤，导致致瘤性改变的积累，并通过巴雷特化生 (BE) 进展为 EA。然而，大多数 GERD 和 BE 患者在没有恶变的情况下康复，只有一小部分继续发展为食管肿瘤。因此，揭示肿瘤进展的机制非常重要，以便能够确定筛查高危患者的靶标，并开发食管肿瘤的新预防疗法。 我们提出了一个创新的假设来研究食管反流损伤情况下 DNA 损伤修复的具体机制，并应用这些知识来设计新的化学预防疗法。这一假设得到了来自人体组织、动物模型和广泛体外研究的强有力的初步数据的支持。我们已经证明p73蛋白在食管肿瘤发生和GERD引起的食管反流损伤条件下DNA损伤修复的调节中发挥着关键作用。我们还发现了一组新的化学预防化合物，它们可以特异性激活 p73 的保护功能并减少反流引起的 DNA 损伤。 我们将在这些发现的基础上进一步研究 p73 和 p53 蛋白家族的其他成员在食管腺癌进展中所发挥的作用。在目标1中，我们将剖析食管反流条件下p73调节的DNA损伤修复机制。在目标 2 中，我们将研究体内食管肿瘤的发生。我们将采用胃食管反流损伤小鼠模型和食管器官型培养物来概括人类 GERD 相关病理学并剖析 DNA 损伤修复机制。这些研究将与人类食管癌前病变和癌病变的分析相补充。在目标 3 中，我们将探索在 GERD 条件下诱导 p73 保护活性的化合物的化学预防潜力。 我们的研究结果将对理解与 GERD 和 BE 相关的多步骤肿瘤发生产生重大影响。重要的是，我们的结果有助于揭示食管肿瘤发生的潜在危险因素，并为高危 GERD 和 BE 患者开发新型化学预防方法奠定基础。