H PYLORI RELATIONSHIP TO DIGESTIVE DISEASES AND CANCER

幽门螺杆菌与消化系统疾病和癌症的关系

• 批准号: 2896500
• 负责人: RICHARD M. PEEK
• 金额: $ 7.03万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896500
• 关键词: Helicobacter; adenocarcinoma; animal genetic material tag; apoptosis; bacterial disease; carcinogenesis; clinical research; disease /disorder etiology; free radical oxygen; gastric mucosa; gastritis; gastrointestinal epithelium; gerbil /jird; host organism interaction; human genetic material tag; human subject; laboratory mouse; neoplasm /cancer genetics; nitric oxide; stomach neoplasms; transcription factor; tumor suppressor proteins

DESCRIPTION (taken from the application) Persistent H. pylori infection is an important etiologic factor for the development of atrophic gastritis and gastric adenocarcinoma; however, only a small percentage of infected persons develop neoplasia. Enhanced cancer risk may be related to differences in expression of specific bacterial products, differences in host response to the bacteria, or both. H. pylori strains that possess cagA are associated with increased severity of gastritis and with additional risk for developing atrophic gastritis and cancer. One mechanism contributing to neoplastic transformation may be inhibition of epithelial cell apoptosis, a process regulated by transcription factors such as NF-KappaB and p53. Our hypothesis is that the increased malignant potential of H. pylori cagA+ strains is dependent on the ability to selectively affect eukaryotic proteins that regulate multiple cellular pathways which results in both heightened inflammation and decreased apoptosis. Since the effect of H. pylori on programmed cell death is likely to be complex, this project is being submitted as one component of an interactive proposal with Dr. Duane Smoot of Howard University. Dr. Smoot's in vitro studies will primarily focus on downstream effectors of NF-KappaB-dependent apoptosis such as nitric oxide, reactive oxygen intermediates, and Bc1-2 related proteins which will complement our experiments on H. pylori and NF-KappaB in gastric epithelial cells and gastric mucosa. This collaborative approach should facilitate elucidation of specific mechanisms by which H. pylori alters apoptosis and predisposes infected individuals to carcinogenesis. The long-term objective of this proposal is to examine the molecular mechanisms by which H. pylori strains selectively affect apoptosis in vitro and in vivo. First, we plan to determine whether wild-type H. pylori strains of varying genotype differentially affect NF-KappaB dependent apoptosis, using an in vitro model of gastric epithelial cell interaction with H. pylori. Using isogenic mutant strains containing inactivation cassettes within cagA, picA, picB, vacA, and iceA, we also will determine the role of specific H. pylori virulence determinants in eukaryotic apoptosis. Second, we will determine the effect of wild-type and isogenic H. pylori mutant strains on gastric epithelial cell apoptosis and NF-KappaB-dependent apoptosis in vivo using a rodent model of infection. Third, we will examine the effect of H. pylori on mediators of gastric epithelial cell apoptosis in vivo in p53-deficient mice. From these studies, as well as from Dr. Smoot's experiments, we can begin to dissect the pathways that are activated in gastric epithelial cells following interaction with H. pylori that may play a role in the subsequent development of gastric cancer.

描述（取自应用程序） 持续性幽门螺杆菌感染是 萎缩性胃炎和胃腺癌的发展；但是，只有 一小部分被感染的人出现肿瘤。 增强的癌症 风险可能与特定细菌表达的差异有关 产品，宿主对细菌的反应差异，或两者兼有。 幽门螺杆菌 拥有CAGA的菌株与严重程度增加有关 胃炎，并具有发展萎缩性胃炎的额外风险和 癌症。 有助于肿瘤转化的一种机制可能是 抑制上皮细胞凋亡，这一过程受 NF-KAPPAB和p53等转录因子。 我们的假设是 幽门螺杆菌CAGA+菌株的恶性潜力增加取决于 能够选择性影响调节多重的真核蛋白 细胞途径导致炎症增加和 凋亡减少。 由于幽门螺杆菌对程序性细胞死亡的影响 很可能很复杂，该项目被提交为 与霍华德大学的Duane Smoot博士的互动提议。 博士 Smoot的体外研究将主要关注 NF-kappab依赖性凋亡，例如一氧化氮，活性氧 中间体和BC1-2相关的蛋白质将补充我们 胃上皮细胞和 胃粘膜。 这种协作方法应该有助于阐明 幽门螺杆菌改变凋亡和易感性的特定机制 感染了癌变的个体。 该提议的长期目标是检查分子 幽门螺杆菌菌株在体外选择性影响凋亡的机制 和体内。 首先，我们计划确定野生型幽门螺杆菌是否 不同基因型的菌株差异地影响NF-kappab依赖性 凋亡，使用胃皮细胞相互作用的体外模型 与幽门螺杆菌。 使用含有灭活的同基因突变菌株 CAGA，PICA，PICB，VACA和ICEA中的盒式磁带，我们还将确定 特异性幽门螺杆菌毒力决定因素在真核的作用 凋亡。 其次，我们将确定野生型和等源性的效果 幽门螺杆菌突变菌株在胃上皮细胞凋亡和 NF-kappab依赖性凋亡在体内使用啮齿动物感染模型。 第三，我们将检查幽门螺杆菌对胃介体的影响 p53缺陷小鼠体内的上皮细胞凋亡。 从这些 研究以及Smoot博士的实验，我们可以开始剖析 随后在胃上皮细胞中激活的途径 与幽门螺杆菌的相互作用，可能在随后发挥作用 胃癌的发展。