Mechanisms of Tumorigenic Transformation of Barretts Esophagus

项目摘要/摘要 食管腺癌(EAC)发病率迅速上升，已成为严重的临床问题。 利率，以及目前可用的有限治疗选择。这种疾病现在已经超过了其他组织学上的疾病。 美国的食道肿瘤类型。EAC的主要危险因素是胃食道反流病。 (GERD)，影响10%至20%的美国人口。在GERD的条件下，食道细胞被分离出来。 摆在酸性胃液中混合十二指肠胆盐。反流暴露会导致慢性炎症， 和过度氧化的DNA损伤，导致肿瘤的改变和进展的积累 通过Barrett化生(BE)转移至EAC。然而，恶性肿瘤背后的精确分子事件 食道细胞的转化仍然知之甚少，从而限制了对靶细胞的识别 高危患者的筛查和食道肿瘤新疗法的开发。 我们提出了一个创新的假说来研究食道细胞的致瘤转化。 在食道反流损伤的情况下。这一假设得到了来自人类的强有力的初步数据的支持 组织、动物模型和广泛的体外研究。我们已经证明了6Np73蛋白在 抑制Barrett‘s食道关键抑癌蛋白在食道肿瘤发生中的关键作用 暴露于慢性胃食道反流的细胞。我们还确定了导致疾病的病理因素 6Np73激活。 我们将在这些发现的基础上，进一步调查6Np73和其他成员所扮演的角色 P53蛋白家族在食管腺癌进展中的作用在目标1中，我们将剖析这些机制 在EAC进展过程中6Np73上调。在目标2中，我们将研究食道肿瘤的发生 活着。我们将采用新的小鼠胃食道反流损伤模型和食道器质性损伤模型。 总结人类GERD相关的病理并剖析6Np73的功能。这些研究将 辅以对人类食道癌前病变和癌病变的分析。在《目标3》中，我们将 探讨胃食道反流所致DNA氧化损伤的生物学调控作用。 我们的发现将对理解与以下因素相关的多步骤肿瘤发生有很大影响 格尔德和贝。重要的是，我们的结果可能有助于揭示食道肿瘤发生的潜在危险因素。 为开发新的化疗方法治疗高危患者奠定了基础 GERD和BE。

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.