Regulation of DNA damage response in esophageal cells exposed to reflux

食管腺癌（EAC）由于发病率的增加而引起严重的临床问题， 有限的治疗选择。已知最强的EAC风险因素之一是胃食管反流病 胃食管反流病（GERD），一种慢性消化疾病，其中来自胃的酸性内容物，经常与Duode- 最终胆汁进入食管，造成食管组织损伤。在细胞水平上，胃食管再- 通量的特征是食管细胞DNA的持续损伤，增加了突变率， 微粒基因组不稳定性。GERD在退伍军人中很常见。然而，只有一部分受影响的人- uals发展成瘤，强调了确定调节肿瘤发生相互作用的机制的重要性， 选择。 我们提出了一个创新的假说来解释持续的反流如何诱导肿瘤发生， 通过抑制DNA损伤反应（DDR）（一种关键的肿瘤抑制因子）， 负责维持基因组完整性的机制。这一假设得到了 动物和人类研究产生的强有力的初步数据。 我们将通过详细说明GERD对DDR的影响来扩展这些新发现。在目标1中，我们将定义 以前未知的分子机制，通过反流抑制DDR。在目标2中，我们将进行调查 利用食管反流损伤动物模型研究食管小生境中DDR的调节。我们也将- 裂解人类临床标本。在目标3中，我们将测试各种备选方案，以避免因 体内GERD。 结合起来，我们的研究将进一步阐明肿瘤发生改变的潜在危险因素， 并为阻止恶性肿瘤发展的新治疗方法奠定基础。 食管病变

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.