Mechanisms of Growth Inhibition by Helicobacter Pylori

描述(由申请人提供)： 幽门螺杆菌是人类免疫缺陷的重要致病因素 消化性溃疡极大地改变了溃疡患者的治疗方式。 在服用抗生素和酸性物质的同时，溃疡愈合得更快 药物治疗。对这种观察的一种可能的解释是细胞 幽门螺杆菌的产生受到损害；因此，溃疡愈合得更快 未发现幽门螺杆菌感染。流行病学研究强烈地表明 幽门螺杆菌与胃癌的发生有关。这些数据引领世界 卫生组织将幽门螺杆菌列为I类致癌物质。这是感觉到的 至少有一半的胃癌是由于感染了这种病毒 细菌。然而，关于幽门螺杆菌是如何直接 作用于胃细胞，导致胃癌。流行病学数据支持 这种细菌是一种辅因子，因为它会引起慢性胃炎，这可能会 肠型胃的前驱病变--萎缩性胃炎的研究进展 癌症。 然而，这种细菌也与弥漫性胃癌有很强的联系 发生在正常(非萎缩性)胃粘膜中，其中细菌 当癌症发生时，感染是存在的。体内研究表明， 一些细菌菌株在没有上升的情况下会造成严重的细胞损伤 在胃细胞凋亡中。一种解释是，细菌在引起细胞 损伤，就是能够下调细胞凋亡。细胞凋亡率的减少 胃细胞损伤是这种细菌可能的一种机制 直接增加胃细胞对致癌物质的易感性 转换。这笔赠款建议评估幽门螺杆菌对 胃上皮细胞的细胞死亡。这个项目的具体目标是 目的是：1)更好地阐明幽门螺杆菌中P53途径的参与 通过测定细胞中P53的磷酸化程度来诱导细胞凋亡 对幽门螺杆菌菌株的暴露和磷酸化的重要性 丝氨酸-15、-20和-46与细胞凋亡有关。此外，评估P53 幽门螺杆菌存在时ROS物种的磷酸化反应 幽门螺杆菌和抗氧化剂的存在。2)确定参与和 磷酸化激活p53AIP1的意义 丝氨酸-46处的P53。细菌对胃上皮细胞的暴露机制 细胞死亡还没有关于P53的研究。这些研究很重要 为了阐明暴露在这种物质中所调节的特定的P53通路 细菌，导致调节细胞死亡。 具体而言，无论H。 幽门螺杆菌对P53的磷酸化是必不可少的，从而导致细胞凋亡。这些研究 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患 罹患癌症。

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.