Differential Transcription Factor Activation by H. pylor

描述（由申请人提供）：幽门螺杆菌（H. pylori）感染极大地改变了我们对上消化道的理解。消化道疾病，包括消化性溃疡和胃癌。世界卫生组织已将H.幽门螺旋杆菌是一组致癌物。活性氧（ROS）是已知的致癌物质，并已被证明在胃癌中发挥作用。我们的研究表明，H. pylori刺激胃细胞内ROS的产生。通过将胃细胞置于促氧化状态，H。幽门螺杆菌增加了ROS导致DNA损伤和癌症发展的风险。上皮细胞通过凋亡保护自身免受DNA损伤。H. pylori诱导的细胞凋亡与NF-κ B和p53的激活有关。还有H。pylori诱导的细胞凋亡与CD 95/Fas通路的刺激有关。我们的初步研究表明，H. pylori感染与p14 ARF表达增加和mdm 2表达下调有关。本研究计划确定p53介导的细胞凋亡和CD 95/Fas介导的细胞凋亡对H. pylori我们假设真核细胞内活性氧的刺激是H. pylori诱导的细胞损伤导致氧化剂相关的DNA损伤和凋亡。我们进一步假设转录因子p53和NF-κ B是暴露于H.幽门。我们最近的研究表明，暴露于H. pylori感染继发于ARF的刺激，ARF通过阻止Mdm 2抑制p53活性和Mdm 2介导的p53降解来稳定p53。因此，ROS可能是ARF刺激导致p53增加的原因。本研究的具体目的是：（1）确定ROS是否导致NF-κ B的活化，NF-κ B可能依赖或不依赖于p53而使胃细胞对凋亡敏感;（2）阐明H. pylori诱导p53蛋白表达增加和细胞凋亡;（3）探讨CD 95（Fas/Apo-1）受体/配体系统在p53增敏H.幽门。鉴定这种细菌激活的转录因子并阐明所涉及的凋亡途径将有助于我们开发更好的治疗策略，以预防这种感染引起的严重疾病。通过保护胃细胞免受ROS的影响，人们可能能够否定这种细菌的致癌特性。

DESCRIPTION (provided by applicant): The discovery of Helicobacter pylori (H. pylori) infection has greatly changed our understanding of upper G.I. tract diseases, including peptic ulcer disease and stomach cancer. The world health organization has classified H. pylori as a group one carcinogen. Reactive oxygen species (ROS) are known carcinogens and have been shown to play a role in gastric cancer. Our studies have shown that H. pylori stimulates the generation of ROS within gastric cells. By placing gastric cells into a pro-oxidant state, H. pylori increases the risk of DNA damage from ROS and the development of cancer. Epithelial cells protect themselves from DNA damage by undergoing apoptosis. H. pylori induce apoptosis is associated with activation of both NF-kappaB and p53. Also H. pylori induced apoptosis is associated with stimulation of the CD95/Fas pathway. Our preliminary studies show that the increase in p53 protein after exposure of gastric cells to H. pylori is associated with increased expression of p14 ARF and down regulation of mdm2. The studies planned in this proposal will identify any interactions between p53 mediated apoptosis and CD95/Fas-mediated apoptosis in response to H. pylori We hypothesize that stimulation of intracellular reactive oxygen species within eukaryotic cells is a major mediator of H. pylori induced cellular injury resulting in oxidant associated DNA damage and apoptosis. We further hypothesize that transcription factors p53 and NF-KappaB are important downstream mediators of ROS induced cellular injury from exposure to H. pylori. Our more recent studies show that the rise in p53 after exposure to H. pylori is secondary to stimulation of ARF which stabilizes p53 by preventing Mdm2 inhibition of p53 activity and Mdm2 mediated degradation of p53. Therefore, ROS may be responsible for stimulation of ARF resulting in increased p53. The specific aims of this proposal are: (1) to determine whether or not ROS leads to activation of NF-KappaB which may sensitize gastric cells to apoptosis, dependent or independent of p53; (2) To elucidate mediators of ARF activation by H. pylori leading to increased p53 protein and apoptosis; (3) To determine the involvement of the CD95 (Fas/Apo-1) receptor/ligand system in p53 sensitization of gastric cells to apoptosis induced by H. pylori. Identification of transcription factors activated by this bacterium and elucidation of apoptotic pathways involved will assist us to develop better treatment strategies to prevent serious disease from this infection. By protecting gastric cells from ROS, one may be able to negate the carcinogenic properties of this bacterium.