Mechanisms of Growth Inhibition by Helicobacter Pylor

幽门螺杆菌生长抑制机制

• 批准号: 6752694
• 负责人: Hassan Ashktorab
• 金额: $ 5.07万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752694
• 关键词: Helicobacter; apoptosis; cancer risk; clinical research; free radical oxygen; gastrointestinal epithelium; host organism interaction; human tissue; p53 gene /protein; phosphorylation; serine; tissue /cell culture

DESCRIPTION (provided by applicant): The discovery that H. pylori is an important factor in the development of peptic ulcers has dramatically changed the way ulcer patients are treated. Ulcers heal faster in persons treated with antibiotics in addition to acid medication. One possible explanation for this observation is that cell generation is impaired by H. pylori; thus, ulcer healing occurs more rapidly in the absence of H. pylori infection. Epidemiological studies have strongly associated H. pylori with gastric carcinogenesis. These data led the World Health Organization to designate H. pylori a Class I carcinogen. It is felt that at least half of all gastric cancers are attributed to infection with this bacterium. However, there is little known as to how H. pylori may directly effect gastric cells to cause gastric cancer. Epidemiological data supports this bacterium as a cofactor because it causes chronic gastritis which may progress to atrophic gastritis, a precursor lesion for intestinal type gastric cancer. However, this bacterium is also strongly linked to diffuse gastric cancer which occurs in otherwise normal (non-atrophic) gastric mucosa, where the bacterial infection is present at the time the cancer occurs. In vivo studies show that some bacterial strains cause significant cell injury in the absence of a rise in gastric apoptosis. One explanation is that the bacterium, while causing cell injury, is able to down regulate apoptosis. The decrease in apoptosis in injured gastric cells is one possible mechanism by which this bacterium might directly increase the susceptibility of gastric cells to carcinogenic conversion. This grant proposes to evaluate the direct effects of H. pylori on the cell death in gastric epithelial cells. The Specific Aims of this project are: 1)To better elucidate the involvement of the p53 pathway in H. pylori induced apoptosis by determining the extent of phosphorylation of p53 in cells exposed to H. pylori strains and the importance of phosphorylation at serine-15,-20 and-46 in regard to apoptosis. Also, to evaluate p53 phosphorylation in response to ROS species in the absence of H. pylori and in the presence of H. pylori and antioxidants. 2)To determine the involvement and significance of activation of p53AIPl, which is activated by phosphorylating p53 at serine-46. The mechnism of bacterial exposure on the gastric epithelial cell death has not been studied in regard to p53. These studies are important to elucidate specific p53 pathways that are modulated by exposure to this bacterium, resulting in an regulating cell death. Specifically, whether or not stimulation of reactive oxygen species (ROS) by H. pylori is essential for p53 phosphorylation leading to apoptosis. These studies will help to establish how bacteria can increase apoptosis possibly through generation of ROS and in specific circumstances this may alter one's risk of developing cancer.

描述（由申请人提供）： 发现幽门螺杆菌是发展的重要因素 消化性溃疡已经大大改变了溃疡患者的治疗方式。 除了酸外，溃疡在接受抗生素治疗的人中更快地治愈 药物。该观察结果的一种可能的解释是细胞 幽门螺杆菌损害发电。因此，溃疡愈合的发生更快 缺乏幽门螺杆菌感染。流行病学研究强烈 相关的幽门螺杆菌与胃癌发生。这些数据引发了世界 卫生组织指定幽门螺杆菌A类致癌。感觉到 至少一半的胃癌归因于此 细菌。但是，众所周知幽门螺杆菌如何直接 影响胃细胞引起胃癌。流行病学数据支持 该细菌作为辅助因子，因为它会导致慢性胃炎 进展到萎缩性胃炎，这是肠类型胃的前体病变 癌症。 但是，该细菌也与弥漫性胃癌密切相关 发生在其他正常（非养分性）胃粘膜中，其中细菌 发生癌症时感染存在。体内研究表明 某些细菌菌株在没有上升的情况下会导致重大细胞损伤 在胃凋亡中。一种解释是细菌，同时引起细胞 受伤，能够降低凋亡。细胞凋亡的减少 受伤的胃细胞是该细菌可能通过的一种可能的机制 直接增加胃细胞对致癌性的敏感性 转换。该赠款建议评估幽门螺杆菌对 胃上皮细胞中的细胞死亡。该项目的具体目的 是：1）更好地阐明p53途径在幽门螺杆菌中的参与 通过确定细胞中p53的磷酸化程度来诱导凋亡 暴露于幽门螺杆菌菌株和磷酸化的重要性 丝氨酸-15，-20和-46关于凋亡。另外，要评估p53 在幽门螺杆菌的情况下，磷酸化对ROS物种的响应和 幽门螺杆菌和抗氧化剂的存在。 2）确定参与和 p53Aipl激活的重要性，通过磷酸化激活 丝氨酸46的p53。细菌暴露于胃皮细胞上的机甲 尚未研究细胞死亡。这些研究很重要 阐明通过暴露于此调节的特定p53途径 细菌，导致调节细胞死亡。 具体而言，H。是否刺激活性氧（ROS）。 幽门螺杆菌对于导致凋亡的p53磷酸化至关重要。这些研究 将有助于确定细菌如何通过 ROS的产生和特定情况下可能会改变自己的风险 发展癌症。