DIFFERENTIAL TRANSCRIPTION FACTOR ACTIVATION BY H PYLORI

描述(取自应用程序) 幽门螺杆菌感染导致慢性胃炎，以及 流行病学研究表明，幽门螺杆菌是一种独立的 胃癌的危险因素。然而，幽门螺杆菌感染的机制 导致上皮细胞损伤，或导致胃癌的发展 还没有被很好地理解。感染幽门螺杆菌的人有3到9倍 与非感染者相比，患胃癌的风险更高。 幽门螺杆菌引起的浅表性胃炎向萎缩性胃炎的进展 胃炎伴肠上皮化生被认为是胃病的先兆 癌症的发展。调查人员推测，天然的 幽门螺杆菌相关性慢性胃炎进展为萎缩性 胃炎，可由细菌因素延长或缩短， 调节胃上皮细胞防御机制。幽门螺杆菌菌株 拥有CAG致病岛的人与 与非胃癌(cagA阴性菌株)相比，有更高的耐药率。幽门螺杆菌 已经被证明可以诱导巨噬细胞的氧化爆发，而且有 感染者胃粘膜诱导型一氧化氮合酶和过氧亚硝酸根含量升高， 以及较少的维生素C。我们推测，幽门螺杆菌可能会增加患病风险 通过与特定转录因子相互作用促进胃癌的发生 (核因子-kappaB、p53)与cagA产生相对的抗凋亡作用 阳性菌株。此赠款是交互式R01/R29赠款的一部分 关于阐明幽门螺杆菌与转录相互作用的建议 核因子-kB和p53，在体外和体内，可能对 细胞凋亡并导致暴露于化学物质中的癌症风险增加 致癌物质和活性氧物种。这项建议的具体目的 是：(1)确定P53的差异调控是否通过 与cagA阴性菌株相反，cagA阳性菌株可导致细胞滞留 在细胞周期的不同阶段；(2)确定是否激活 CagA阳性菌株中的核因子-kB与细胞凋亡减少有关 对幽门螺杆菌细胞损伤的反应，以及这是否涉及 抑制P53依赖的细胞凋亡和/或刺激通路 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，包括原代培养的正常人 胃上皮细胞与SV-40转化的非恶性人 胃上皮细胞株。体内研究将作为以下项目的一部分进行 由Peek博士提出的R01/R29交互式提案，他将使用已建立的 可感染幽门螺杆菌的动物模型。这些研究将 阐明幽门螺杆菌可改变的胃细胞内通路 并展示了这种细菌可能通过哪些潜在机制增加 胃上皮细胞对致癌物DNA损伤的敏感性。

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.