Role of Fas/NF kB in H.pylori induced gastric carcinoma

描述：(申请人提供)幽门螺杆菌感染导致 胃和十二指肠病变的范围从过度增殖和 腺癌到严重的组织丢失(溃疡)。细菌是如何引起这些的 自相矛盾的疾病后果尚不清楚。最近的研究，包括 我们实验室的研究表明，Fas凋亡信号在 在幽门螺杆菌所致溃疡发病机制中的重要作用 启动细胞死亡程序。此外，初步结果强劲。 提示Fas信号通路在调节胃功能中起直接作用 通过诱导粘膜细胞增殖(除细胞死亡外) 核因子-kB。核因子激活被认为是积极调节的 细胞增殖和促进生存，潜在地允许突变 在异常增殖的细胞内导致癌症的形成。这个 本申请中提出的实验旨在确定 Fas诱导胃上皮细胞异常增殖的机制。我们 L L确定Fas信号转导的机制 增殖性反应与成熟成分的特殊作用 Fas途径在引发这种反应中的作用。为了实现这些目标，我们 将改造胃粘膜细胞系以转导增殖 通过控制Fas抗原的表达(结构性的或诱导性的)来传递信号。 这种方法之后将采用基因敲除策略来分离角色 参与这一反应的候选信号分子的数量。这些信息 在受控试管环境中获得的将用于开发 以及体外模型的表征。新设计的Fas的开发 银杏叶提取物和Fas L缺乏辐射嵌合体的小鼠模型较为复杂， 严谨和临床相关的活体胃粘膜环境将 允许研究Fas增殖信号的重要性。 允许异常增殖的机制可能有助于癌症的发生 通过抑制死亡和促进细胞分裂 累积的遗传缺陷。定义这些途径的调节将 帮助确定幽门螺杆菌与宿主之间的复杂关系。

DESCRIPTION: (provided by Applicant) Helicobacter pylori infection causes a spectrum of gastric and duodenal pathology ranging from hyperproliferation and adenocarcinoma to severe tissue loss (ulcers). How the bacterium causes these paradoxical disease outcomes is not understood. Recent studies, including those from our laboratory, have shown that Fas apoptotic signaling plays a significant role in the pathogenesis of helicobacter-induced ulcer disease by initiating cell death programs. In addition, preliminary results strongly suggest a direct role for the Fas signaling pathway in modulating gastric mucosal cell proliferation (in addition to cell death) through induction of NF-kB. Nuclear factor activation has been suggested to positively regulate cell proliferation and promote survival, potentially allowing for mutations within abnormally proliferating cells leading to cancer formation. The experiments proposed in this application are aimed at determining the role and mechanism of Fas-induced aberrant gastric epithelial cell proliferation. We w i l l determine the mechanism of modulating Fas signaling towards a proliferative response and the specific roles of well established components of the Fas pathway in eliciting this response. To accomplish these goals, we will engineer gastric mucosal cell lines which transduce proliferative signaling by manipulating Fas Ag expression (constitutively or inducibly). This approach will be followed with gene-knockout strategies to isolate roles of candidate signaling molecules that mediate this response. The information gained in the controlled in vitro setting will be utilized for the development and characterization of in vitro models. Exploitation of newly engineered Fas Ag and Fas L deficient radiation chimera murine models as a more complex, rigorous and clinically relevant in vivo gastric mucosal environment will allow for the study of the importance of Fas proliferative signaling. Mechanisms which allow aberrant proliferation may contribute to carcinogenesis by inhibiting death and promoting cell division in cells which have accumulated genetic defects. Defining the regulation of these pathways will help define the complex relationship helicobacter shares with its host.