Regulation of DNA damage response in esophageal cells exposed to reflux

食管腺癌(EAC)是一种严重的临床问题，其发病率和发病率不断增加。 治疗选择有限。已知的EAC最强烈的危险因素之一是胃食道反流病 (GERD)，一种慢性消化状态，胃中的酸性内容物经常与十二指肠混合- 胆汁，进入食道导致食道组织损伤。在细胞水平上，胃食道重新- 通量的特征是对食道细胞DNA的持续损伤，从而增加突变率和促进 尘埃基因组不稳定。Gerd在退伍军人中很常见。然而，只有一部分受影响的个人- UAL发展成肿瘤，强调了定义调节肿瘤形成相互作用的机制的重要性。 特兹。 我们开发了一个创新的假说来解释持续的返流是如何导致肿瘤的替代的。 抑制关键的肿瘤抑制因子DNA损伤反应(DDR)在食道中的作用 负责维持基因组完整性的机制。这一假设得到了 由动物和人类研究产生的强大的初步数据。 我们将通过详细说明GERD对DDR的影响来扩展这些新颖的发现。在目标1中，我们将定义 反流抑制DDR的分子机制尚不清楚。在目标2中，我们将调查 利用食道反流损伤动物模型研究DDR对食管龛的调节作用。我们还将分析- 裂解人体临床标本。在目标3中，我们将测试各种方案，以避免抑制由 GERD在体内。 总而言之，我们的研究将进一步阐明肿瘤发生变化的潜在危险因素。 并为阻止恶性发展的新的治疗方法奠定了基础 食道损伤。

Esophageal adenocarcinoma (EAC) poses a serious clinical problem due to the increasing incidence and limited treatment options. One of the strongest known risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duode- nal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, gastroesophageal re- flux is characterized by continuous damage to esophageal cell DNA that increases the mutation rate and pro- motes genomic instability. GERD is common among veterans. However, only a percentage of affected individ- uals develop neoplasia, underscoring the importance of defining mechanisms that regulate tumorigenic interac- tions. We have developed an innovative hypothesis to explain how continued reflux induces tumorigenic altera- tions in the esophagus through inhibition of the DNA Damage Response (DDR), a critical tumor suppressor mechanism that is responsible for maintaining the integrity of the genome. This hypothesis is supported by strong preliminary data generated by animal and human studies. We will expand on these novel findings by detailing the impact of GERD on the DDR. In aim 1, we will define previously unknown molecular mechanisms through which reflux inhibits the DDR. In aim 2, we will investigate the DDR regulation in the esophageal niche using animal models of esophageal reflux injury. We will also ana- lyze human clinical specimens. In aim 3, we will test various options to avert inhibition of the DDR induced by GERD in vivo. Combined, our studies will further elucidate the potential risk factors for tumorigenic alterations in the esophagus and lay the groundwork for novel therapeutic approaches that halt the development of malignant esophageal lesions.