Mechanisms of Tumorigenic Transformation of Barretts Esophagus

Barretts食管致瘤转化机制

• 批准号: 9248180
• 负责人: ALEXANDER I. ZAIKA
• 金额: $ 27.71万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248180
• 关键词: Mechanisms; Tumorigenic; Transformation; Barretts; Esophagus

PROJECT SUMMARY/ABSTRACT Esophageal adenocarcinoma (EAC) is a serious clinical problem due to its 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 EAC 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 mixed with duodenal bile salts. The reflux exposure causes chronic inflammation, and excessive oxidative DNA damage, resulting in the accumulation of tumorigenic alterations and progression to EAC through Barrett's metaplasia (BE). However, the precise molecular events underlying the malignant transformation of esophageal cells remain poorly understood, thereby limiting the identification of targets for screening at risk patients and the development of new therapies for esophageal tumors. We have developed an innovative hypothesis to investigate tumorigenic transformation of esophageal cells in conditions of esophageal reflux injury. This hypothesis is supported by strong preliminary data from human tissues, animal models, and extensive in vitro studies. We have demonstrated that the 6Np73 protein plays a critical role in esophageal tumorigenesis by inhibiting key tumor suppressor proteins in Barrett's esophageal cells exposed to chronic gastroesophageal reflux. We have also identified pathological factors that lead to 6Np73 activation. We will build on these findings to further investigate the role played by 6Np73 and other members of the p53 protein family in the progression to esophageal adenocarcinoma. In aim 1, we will dissect the mechanisms of 6Np73 upregulation during progression to EAC. In aim 2, we will investigate esophageal tumorigenesis in vivo. We will employ novel mouse model of gastroesophageal reflux injury and esophageal organotypic cul- tures to recapitulate human GERD-associated pathology and dissect the function of 6Np73. These studies will be complemented with analyses of human esophageal precancerous and cancerous lesions. In aim 3, we will explore the biological functions in the regulation of oxidative DNA damage induced by gastroesophageal reflux. 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 devel- opment and lay the groundwork for development of novel chemotherapeutic approaches in at risk patients with GERDand BE.

项目摘要/摘要 食管腺癌（EAC）是一个严重的临床问题，因为它的发病率迅速增加 费率和当前可用的有限治疗方案。现在，这种疾病已超过其他组织学 美国食管肿瘤的类型。 EAC的主要危险因素是胃食管反流疾病 （GERD），影响美国人口的10％至20％。在GERD的条件下，食管细胞是 与十二指肠胆汁盐混合的酸性胃汁。反流暴露会导致慢性炎症， 和过多的氧化DNA损伤，导致肿瘤改变和进展的积累 通过Barrett的Metaplasia（BE）来依次。但是，恶性肿瘤的确切分子事件 食管细胞的转化仍然很了解，从而限制了识别目标 在风险患者中筛查和食管肿瘤的新疗法的发展。 我们已经开发了一种创新的假设来研究食管细胞的肿瘤性转化 在食管反流损伤的情况下。该假设得到了人类的强大初步数据的支持 组织，动物模型和广泛的体外研究。我们已经证明6NP73蛋白在 通过抑制巴雷特食管中的关键抑制肿瘤蛋白，在食管肿瘤发生中的关键作用 暴露于慢性胃食管反流的细胞。我们还确定了导致的病理因素 6NP73激活。 我们将基于这些发现，以进一步研究6NP73和其他成员的作用 p53蛋白家族在食管腺癌的进展中。在AIM 1中，我们将剖析机制 在向EAC进展过程中的6NP73上调的上调。在AIM 2中，我们将研究食管肿瘤发生 体内。我们将采用新型的胃食管反流损伤的小鼠模型和食管的器官cul- 概括与人类GERD相关的病理学并剖析6NP73的功能。这些研究会 与人类食管前癌病变和癌性病变的分析相辅相成。在AIM 3中，我们将 探索胃食管反流引起的氧化DNA损伤调节的生物学功能。 我们的发现将对与与之相关的多步肿瘤发生的理解产生强烈的影响 Gerd和Be。重要的是，我们的结果可能有助于揭示食管肿瘤开发的潜在危险因素 Opment并为开发新型化学治疗方法的发展奠定了基础 Gerdand是。