Helicobacter pylori CagA toxin polymorphism

 描述(申请人提供)：幽门螺杆菌慢性感染超过50%的世界人口，是胃炎、消化性溃疡疾病和胃癌的一个重要原因在胃壁龛内，该细菌与宿主细胞相互作用，并阐述了一些影响疾病病因学的毒力因素。这些致病决定因素中最主要的是细胞毒素相关基因A产物CagA，这是一种通过IV型分泌系统注入宿主细胞的蛋白质。一旦进入宿主细胞，CagA就被宿主细胞的Src/Lyn激酶磷酸化，随后通过与Src同源区2、磷酸酶2(SHP-2)的相互作用和多条信号通路的中断而改变宿主细胞的生理。这些变化被认为是幽门螺杆菌引起的疾病发展的核心，因为流行病学数据表明，感染CagA阳性菌株的人比携带CagA阴性菌株的人更有可能发展为严重的胃病。此外，CagA的C末端部分在经历酪氨酸磷酸化的区域是多态的。流行病学证据和体外组织培养研究表明，这种天然的CagA多态可能是感染个体易患胃癌的关键决定因素。然而，所有将CagA多态与幽门螺杆菌对宿主细胞途径的调节增强联系在一起的细胞培养研究要么使用了非同基因菌株，要么依赖于转染模型。这些研究结果的解释是复杂的，因为H.Pylori显示了非常高的菌株变异，而转基因研究可能不能准确地模拟CagA在自然感染过程中的细菌输送。我们实验室设计并构建了仅在CagA蛋白的C末端磷酸化结构域上存在差异的Hp等基因菌株，在此，我们建议使用这些新菌株来帮助我们通过使用短期胃癌小动物模型来确定CagA基因多态性在宿主细胞变化和疾病发展中的作用，从而帮助我们了解Hp的发病机制。

 DESCRIPTION (provided by applicant): H. pylori chronically infects more than 50% of the world's population and is a significant cause of gastritis, peptic ulcer disease and gastric cancer Within the gastric niche, the bacterium interacts with host cells and elaborates a number of virulence factors that influence disease etiology. Chief among these pathogenic determinants is the cytotoxin-associated gene A product, CagA, a protein that is injected into host cells via a Type IV secretion system. Once inside host cells, CagA is tyrosine phosphorylated by host cell Src/Lyn kinases and subsequently alters host cell physiology via interaction with Src homology region 2, phosphatase 2 (SHP-2) and disruption of multiple signaling pathways. These changes are believed to be central to development of H. pylori-induced disease since epidemiological data indicate that persons infected with CagA-positive strains of H. pylori are significantly more likely to develop severe forms of gastric disease than individuals who harbor CagA-negative isolates. Additionally, the C-terminal portion of CagA is polymorphic specifically in the region that undergoes tyrosine phosphorylation. Epidemiologic evidence and in vitro tissue culture studies indicate that this natural CagA polymorphism may be a crucial determinant for the predisposition of infected individuals to develop gastric cancer. However, all of the cell culture studies that have linked CagA polymorphism to enhanced H. pylori modulation of host cell pathways have either used nonisogenic strains of H. pylori or relied upon transfection models. Interpretation of these study results is complicated by the fact that H. pylori shows a remarkably high degree of strain variation, and transfection studies likely do not accurately mimic bacterial delivery of CagA during the course of a natural infection. Our lab has designed and constructed isogenic strains of H. pylori that differ only in the C-terminal phosphorylation domain of the CagA protein and herein we propose to use these novel strains to aid our long term goal of understanding H. pylori pathogenesis by defining the role of CagA polymorphism in host cell changes and disease development using a short-term gastric cancer small animal model.