Regulation of DNA damage response in esophageal cells exposed to reflux

反流食管细胞 DNA 损伤反应的调节

• 批准号: 10012259
• 负责人: ALEXANDER I. ZAIKA
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012259
• 关键词: Affect; Animal Model; Animal Testing; Animals; Apoptosis; Bile fluid; Biological Process; Cell Cycle Arrest; Cell Proliferation; Cells; Chemicals; Chemopreventive Agent; Chronic; Clinical; DNA; DNA Damage; DNA Repair; DNA Sequence Alteration; Data; Development; Duct (organ) structure; Duodenum; Epithelial; Esophageal Adenocarcinoma; Esophageal Intraepithelial Neoplasia; Esophageal Tissue; Esophageal mucous membrane; Esophagus; Exposure to; Frequencies; Gastroesophageal reflux disease; Genomic Instability; Health; High Prevalence; Histologic; Human; Incidence; Individual; Inflammatory; Injury; Innate Immune Response; Laboratories; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Metaplasia; Molecular; Mutation; Neoplasms; Neoplastic Cell Transformation; PTGS2 gene; Pathway interactions; Patients; Play; Population; Prevention; Protein Family; Proteins; Reflux; Regulation; Reporting; Research; Risk; Risk Factors; Role; Specimen; Stomach Content; Survival Rate; TP53 gene; Testing; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Veterans; adduct; base; chemotherapeutic agent; drug testing; free radical oxygen; genome integrity; in vivo; innovation; insight; interest; member; mouse model; novel; novel therapeutic intervention; premalignant; prevent; response; screening; tissue injury; tumor; tumorigenesis; tumorigenic

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.

食管腺癌（EAC）由于发病率不断增加而造成严重的临床问题。 治疗选择有限。 EAC 已知的最强危险因素之一是胃食管反流病 （GERD），一种慢性消化疾病，胃中的酸性物质经常与十二指肠混合 胆汁进入食管，导致食管组织损伤。在细胞水平上，胃食管重新 Flux的特点是对食管细胞DNA的持续损伤，增加了突变率并促进 微粒基因组不稳定。 GERD 在退伍军人中很常见。然而，只有一小部分受影响的个人 uals 发展为肿瘤，强调了定义调节致瘤相互作用的机制的重要性 系统蒸发散。 我们提出了一个创新的假设来解释持续的反流如何诱导致瘤性改变 通过抑制 DNA 损伤反应 (DDR)（一种重要的肿瘤抑制因子）来抑制食道中的疾病 负责维持基因组完整性的机制。这一假设得到了支持 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 以前未知的反流抑制 DDR 的分子机制。在目标 2 中，我们将调查 使用食管反流损伤动物模型研究食管微环境中的 DDR 调节。我们还将分析- 裂解人类临床标本。在目标 3 中，我们将测试各种选项来避免由以下因素引起的 DDR 抑制： 体内胃食管反流病。 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。 食管，并为阻止恶性食管发展的新治疗方法奠定基础 食管病变。