DIFFERENTIAL TRANSCRIPTION FACTOR ACTIVATION BY H PYLORI

描述（取自应用程序） H.胃幽门螺杆菌感染引起慢性胃炎， 流行病学研究表明H.幽门螺杆菌是一种独立的 胃癌的危险因素。然而，H.幽门 导致上皮细胞损伤，或导致胃癌的发展 并没有得到很好的理解。感染H. pylori有3到9倍的 患胃癌的风险比未感染的人高。 由H.幽门萎缩 伴有肠上皮化生的胃炎被认为是胃溃疡的前兆。 癌症发展研究人员推测， H的进展。幽门相关性慢性胃炎是萎缩性的 胃炎，这可能是延长或缩短的细菌因素，可以 调节胃上皮防御机制。H.幽门螺杆菌菌株， 具有cag致病岛者与 胃癌，比那些没有（cagA阴性菌株）。H.幽门 已显示诱导巨噬细胞的氧化爆发， 感染者胃粘膜中iNOS和过氧亚硝酸盐增加， 沿着较少的维生素C。我们假设H.幽门螺杆菌可能会增加风险 通过与特异性转录因子相互作用 （NF-κ B，p53）导致对cagA凋亡的相对抗性 阳性菌株该补助金是互动R 01/R29补助金的一部分 建议阐明H. pylori与转录 因子NF-κ B和p53，在体外和体内，这可能会产生负面影响， 细胞凋亡，并导致暴露于化学物质 致癌物和活性氧。本提案的具体目标 （1）确定p53的差异调节是否通过 与cagA阴性菌株相反，cagA阳性菌株导致细胞停滞 在细胞周期的不同阶段;（2）为了确定是否激活 cagA阳性菌株的NF-kB与细胞凋亡减少有关， 响应H。幽门螺杆菌细胞损伤，以及这是否涉及 抑制p53依赖性细胞凋亡途径和/或刺激 bc1-2。研究还将着眼于iNOS刺激的潜在影响， 在这种情况下防止细胞凋亡。我们的实验将利用人类 胃上皮细胞，包括正常人的原代培养物 胃上皮细胞和SV-40转化的非恶性人类 胃上皮细胞系体内研究将作为 Peek博士的交互式R 01/R29提案，他将使用现有的 可以感染H.幽门。这些研究将 阐明胃细胞内的途径，可以改变H。幽门 并展示了这种细菌可能增加 胃上皮细胞对致癌物DNA损伤的易感性。

DESCRIPTION (taken from the application) H. pylori infection of the stomach causes chronic gastritis, and epidemiological studies have demonstrated that H. pylori is an independent risk factor for gastric cancer. However, the mechanisms by which H. pylori causes epithelial cell injury, or leads to the development of gastric cancer is not well understood. People infected with H. pylori have a 3 to 9 fold higher risk of developing gastric cancer than non-infected persons. Progression from superficial gastritis caused by H. pylori to atrophic gastritis with intestinal metaplasia is felt to be a precursor to gastric cancer development. Investigators have postulated that the natural progression of H. pylori-associated chronic gastritis is to atrophic gastritis, which may be prolonged or shortened by bacterial factors that can modulate gastric epithelial defense mechanisms. H. pylori strains that possess the cag pathogenicity island are more strongly associated with gastric cancer, than those that do not (cagA-negative strains). H. pylori has been shown to induce oxidative bursts from macrophages and there is increased iNOS and peroxynitrite in the gastric mucosa in infected persons, along with less vitamin C. We postulate that H. pylori may increase the risk of gastric cancer by interacting with specific transcription factors (NF-kappaB, p53) resulting in a relative resistance to apoptosis with cagA positive strains. This grant is part of an interactive R01/R29 grant proposal to elucidate interactions between H. pylori and transcription factors NF- kB and p53, in vitro and in vivo, which may impact negatively on apoptosis and lead to increased cancer risk from exposure to chemical carcinogens and reactive oxygen species. The specific aims of this proposal are: (1) to determine if the differential regulation of p53 by cagA-positive as opposed to cagA-negative strains results in arresting cells at different phases of the cell cycle; (2) To determine if activation of NF-kB by cagA-positive strains is associated with decreased apoptosis in response to H. pylori cell injury, and whether or not this involves inhibition of p53 dependent pathways of apoptosis and/or stimulation of bc1-2. Studies will also look at the potential impact of iNOS stimulation in preventing apoptosis in this setting. Our experiments will utilize human gastric epithelial cells and include primary cultures of normal human gastric epithelial cells and an SV-40 transformed non-malignant human gastric epithelial cell line. In vivo studies will be performed as part of this interactive R01/R29 proposal by Dr. Peek, who will use established animal models which can be infected with H. pylori. These studies will elucidate pathways within gastric cells which can be altered by H. pylori and show potential mechanisms by which this bacteria may increase the susceptibility of gastric epithelial cells to DNA damage from carcinogens.