Helicobacter pylori CagA toxin polymorphism

幽门螺杆菌CagA毒素多态性

基本信息

批准号：
9252373
负责人：
D. SCOTT MERRELL
金额：
$ 19.05万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9252373
关键词：
Affect Alleles Animal Model Animals Bacteria C-terminal Cell Culture Techniques Cell Line Cell physiology Cells Chronic Cytotoxin Development Disease Dysplasia Epidemiology Etiology Gastritis Genes Genetic Polymorphism Gerbils Goals Helicobacter Infections Helicobacter pylori Human In Vitro Individual Infection Inflammation Inflammatory Response Injectable Link MAPK14 gene MAPK8 gene MDCK cell Malignant Neoplasms Mediating Modeling Monitor Oncoproteins Pathogenesis Pathogenicity Pathway interactions Peptic Ulcer Persons Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Population Predisposition Proteins Role STAT3 gene Signal Pathway Signal Transduction Stomach Stomach Diseases Testing Time Tissues Toxin Transfection Type IV Secretion System Pathway Tyrosine Tyrosine Phosphorylation Variant Virulence Factors Work beta catenin cohort design design and construction epidemiologic data global health malignant stomach neoplasm novel novel therapeutics pathogen public health relevance tissue culture

项目摘要

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.

描述（由申请人提供）：幽门螺杆菌长期感染世界上超过 50% 的人口，是胃炎、消化性溃疡病和胃癌的重要原因。在胃壁微环境中，该细菌与宿主细胞相互作用，并产生多种作用。影响疾病病因的毒力因素主要是细胞毒素相关基因 A 的产物 CagA，这是一种注射到宿主体内的蛋白质。一旦进入宿主细胞，CagA 就会被宿主细胞 Src/Lyn 激酶磷酸化，随后通过与 Src 同源区 2、磷酸酶 2 (SHP-2) 相互作用并破坏多种信号传导来改变宿主细胞生理学。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幽门螺杆菌 CagA 阳性菌株的人是与携带 CagA 阴性分离株的个体相比，CagA 的 C 末端部分特别是在发生酪氨酸磷酸化的区域中具有多态性，流行病学证据和体外组织培养表明这一点。天然 CagA 多态性可能是感染个体罹患胃癌的关键决定因素，然而，所有细胞培养研究都将 CagA 多态性与幽门螺杆菌增强联系起来。幽门螺杆菌对宿主细胞途径的调节要么使用幽门螺杆菌的非等基因菌株，要么依赖于转染模型。幽门螺杆菌表现出异常高程度的菌株变异，而转染研究可能没有这种情况，因此这些研究结果的解释变得复杂。准确模拟自然感染过程中 CagA 的细菌传递我们的实验室设计并构建了幽门螺杆菌的同基因菌株，其差异仅在于 CagA 蛋白的 C 末端磷酸化结构域。在此，我们建议使用这些新菌株来帮助我们了解幽门螺杆菌发病机制的长期目标，通过使用短期胃癌小动物模型来定义 CagA 多态性在宿主细胞变化和疾病发展中的作用。