Mechanisms of Growth Inhibition by Helicobacter Pylor

描述（由申请人提供）： 发现H.幽门螺杆菌是一个重要因素的发展， 消化性溃疡已经极大地改变了溃疡患者的治疗方式。 溃疡愈合速度更快的人治疗抗生素除了酸 药对这一观察结果的一种可能解释是， H.幽门;因此，溃疡愈合速度更快， H的缺失。幽门感染流行病学研究强烈表明， 相关H. pylori与胃癌的关系这些数据使世界 卫生组织指定H。pylori是I类致癌物。有人认为 至少有一半的胃癌是由于感染了这种 细菌。然而，很少有人知道H。幽门螺杆菌可能直接 影响胃细胞导致胃癌。流行病学数据支持 这种细菌作为辅因子，因为它会导致慢性胃炎， 进展为萎缩性胃炎，肠型胃癌的前驱病变 癌 然而，这种细菌也与弥漫性胃癌密切相关， 发生在其他正常（非萎缩性）胃粘膜中，其中细菌 在癌症发生时就存在感染。体内研究表明， 一些细菌菌株在没有升高的情况下引起显著的细胞损伤 在胃细胞凋亡中的作用一种解释是，这种细菌在引起细胞凋亡的同时， 损伤，能够下调细胞凋亡。细胞凋亡的减少， 受损的胃细胞是这种细菌可能 直接增加胃细胞对致癌物质的易感性 转换.该基金旨在评估H的直接影响。幽门 胃上皮细胞的细胞死亡。本项目的具体目标 目的：1）进一步阐明p53通路在H.幽门 通过测定细胞中p53的磷酸化程度诱导细胞凋亡 暴露于H.幽门螺杆菌菌株和磷酸化的重要性， 丝氨酸-15、-20和-46在细胞凋亡方面。此外，为了评估p53 在不存在H的情况下，响应于ROS种类的磷酸化。幽门螺杆菌和 H.幽门螺杆菌和抗氧化剂。2）确定参与和 通过磷酸化激活p53 AIP 1的意义 p53丝氨酸-46。细菌暴露对胃上皮细胞的作用机制 关于p53还没有研究细胞死亡。这些研究很重要 为了阐明特定的p53通路， 细菌，导致调节细胞死亡。 特别是，无论是否刺激活性氧（ROS）的H。 pylori是p53磷酸化导致细胞凋亡所必需的。这些研究 这将有助于确定细菌如何可能通过 ROS的产生，在特定情况下，这可能会改变一个人的风险， 发展成癌症

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.