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: 10514576
• 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/10514576
• 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; Duodenum; Epithelium; 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; 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; 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）由于发病率增加而提出了严重的临床问题 有限的治疗选择。 EAC最强的已知危险因素之一是胃食管反流疾病 （GERD）是一种慢性消化条件，其中胃中的酸性含量经常与duode- nal胆汁，进入食道，导致食道组织损伤。在细胞水平，胃食管反应 通量的特征是对食管细胞DNA的连续损害，从而增加了突变率和促进 MOTES基因组不稳定性。 GERD在退伍军人中很常见。但是，只有一定比例的受影响的个体 - UALS发生肿瘤，强调定义调节肿瘤性间间质体的机制的重要性 tions。 我们已经开发了一种创新的假设，以解释持续反流如何引起肿瘤性替代 通过抑制DNA损伤反应（DDR），食管中的tions是一种关键的肿瘤抑制剂 负责维持基因组完整性的机制。该假设得到 动物和人类研究产生的强大初步数据。 我们将通过详细介绍GERD对DDR的影响来扩展这些新颖的发现。在AIM 1中，我们将定义 以前未知的分子机制通过回流抑制DDR。在AIM 2中，我们将调查 食管反流损伤动物模型中食管菌群中的DDR调节。我们还将 Lyze人类临床标本。在AIM 3中，我们将测试各种选择，以避免抑制由 gerd in Vivo。 结合在一起，我们的研究将进一步阐明肿瘤性改变的潜在风险因素 食道并为新的治疗方法奠定了基础，以阻止恶性肿瘤的发展 食管病变。