GI MUCOSAL BARRIER IN HEALTH AND SURGICAL DISEASE

健康和外科疾病中的胃肠道粘膜屏障

• 批准号: 2752262
• 负责人: Susan J Hagen
• 金额: $ 39.3万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2752262
• 关键词: BCL2 gene /protein; CD95 molecule; Helicobacter; acid base balance; adenosine triphosphate; ammonia; apoptosis; biological signal transduction; cell biology; cell migration; cell morphology; cytotoxicity; electron microscopy; gastric mucosa; gastrointestinal infection; guinea pigs; host organism interaction; immunocytochemistry; intestinal mucosa; laboratory rabbit; mitochondria; necrosis; tissue /cell culture; wound healing

The major thrust of the proposed work will be to identify, at the cellular level, mechanisms by which surface and other epithelial cells of the stomach are injured and are repaired in circumstances commonly encountered in daily life. Simultaneously, factors which affect such injuries, both favorably and adversely, will be evaluated. Of special interest are those circumstances which influence cell migration after injury and those which allow or facilitate death of gastric epithelial cells. Finally, since H. pylori infection has such far-reaching implications in terms of benign and malignant disease, the process by which H. pylori infection alters epithelial cells to facilitate cell death and survival will be examined in detail. The investigations will be directed toward the following: a) To further understanding of wound repair after injury with particular reference to the role of intracellular pH, cell volume, and intracellular signaling pathways regulated by Rho, Rac, and Cdc42 in the migration of cultured gastric (surface) epithelial cells. In addition, to define the way in which factors associated with H. pylori infection, such as vacuolating cytotoxin and ammonia, affect restitution (in vitro) and the migration of cultured gastric epithelial cells after injury. b) To define the cytotoxic effects of factors associated with H. pylori infection, such as vacuolating cytotoxin and ammonia, on gastric epithelial cells. Specifically, whether exposure of cultured gastric parietal, chief, or surface cells to these toxins causes severe ATP depletion (by affecting mitochondrial respiration) resulting in either necrotic or apoptotic death. c) To evaluate the expression of cell death and cell survival proteins, such as Fas, Fas Ligand, Bcl-2, and Bax in normal gastric epithelial cells and to determine whether infection with H. pylori modulates the expression of these proteins to result in either accelerated cell death or prolonged cell survival.

拟议工作的主要目标是在细胞水平上确定胃表面和其他上皮细胞在日常生活中常见情况下受伤和修复的机制。同时，将对此类伤害产生有利和不利影响的因素进行评估。 特别令人感兴趣的是那些影响损伤后细胞迁移的情况以及那些允许或促进胃上皮细胞死亡的情况。 最后，由于幽门螺杆菌感染对良性和恶性疾病具有如此深远的影响，因此将详细检查幽门螺杆菌感染改变上皮细胞以促进细胞死亡和存活的过程。研究将针对以下方面：a) 进一步了解损伤后的伤口修复，特别是细胞内 pH、细胞体积以及 Rho、Rac 和 Cdc42 调节的细胞内信号通路在培养胃迁移中的作用（表面）上皮细胞。 此外，确定与幽门螺杆菌感染相关的因素（例如空泡细胞毒素和氨）影响损伤后培养的胃上皮细胞的恢复（体外）和迁移的方式。 b) 确定与幽门螺杆菌感染相关的因素（例如空泡细胞毒素和氨）对胃上皮细胞的细胞毒性作用。具体来说，培养的胃壁细胞、主细胞或表面细胞暴露于这些毒素是否会导致严重的 ATP 耗竭（通过影响线粒体呼吸），从而导致坏死或凋亡。 c) 评估正常胃上皮细胞中细胞死亡和细胞存活蛋白的表达，例如 Fas、Fas Ligand、Bcl-2 和 Bax，并确定幽门螺杆菌感染是否会调节这些蛋白的表达，从而导致要么加速细胞死亡，要么延长细胞存活。