Regulation of gastroesophageal reflux-associated tumorigenesis

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，因为它的发病率高且迅速增加，而且目前可用的治疗方案有限。在美国，这种疾病现在已经超过了其他组织类型的食道肿瘤。EA的主要危险因素是胃食道反流病(GERD)，该疾病影响着美国10%至20%的人口。在GERD条件下，食道细胞暴露于酸性胃液中，常与十二指肠胆汁酸混合。反流暴露会导致慢性炎症和过度的组织和DNA损伤，导致肿瘤形成的变化积累，并通过巴雷特化生(BE)发展为EA。然而，大多数GERD和BE患者重新覆盖后没有恶变，只有一小部分人继续发展为食道肿瘤。因此，重要的是要揭示肿瘤进展的机制，以便能够确定筛查高危患者的靶点，并开发新的食道肿瘤预防性治疗方法。我们开发了一个创新的假说来研究食道反流损伤条件下DNA损伤修复的特定机制，并将这一知识应用于设计新的化学预防疗法。这一假设得到了来自人体组织、动物模型和广泛的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GERD引起的食道反流损伤条件下，在食道肿瘤的发生和DNA损伤修复的调节中起着关键作用。我们还鉴定了一组新的化学预防化合物，它们可以特异性地激活p73的保护功能，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和其他P53蛋白家族成员在食管腺癌进展过程中所起的作用。在目标1中，我们将剖析p73在食道反流条件下调节DNA损伤修复的机制。在目标2中，我们将研究体内食道肿瘤的发生。我们将使用胃食道反流损伤小鼠模型和食道器官培养来概括人类GERD相关的病理，并剖析DNA损伤修复的机制。这些研究将与人类食道癌前病变和癌病变的分析相辅相成。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。我们的发现将对理解与GERD和BE相关的多步骤肿瘤发生有很大的影响。重要的是，我们的结果可以帮助揭示食道肿瘤发生的潜在危险因素，并为开发新的GERD和BE高危患者的化学预防方法奠定基础。

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.