GENETIC AND CELLULAR BASIS OF H. PYLORI PATHOGENESIS

描述（改编自申请人的摘要）：所提出的目标 研究是为了更好地了解H.幽门螺杆菌及其 人类宿主H.幽门是胃炎和溃疡病的病原体， 感染是胃溃疡发生的重要危险因素 癌在以前的研究中，这些研究人员已经表明，H。幽门螺杆菌CagA 被转运到宿主细胞中，然后在酪氨酸上磷酸化 残基通过宿主细胞激酶活性。CagA插入宿主细胞 其随后的磷酸化作用与细胞的重组有关， 宿主细胞骨架，以及宿主细胞形态的巨大变化。 研究人员建议检查CagA插入宿主细胞， CagA插入后的事件顺序。此外，他们建议， 通过突变改变CagA的结构以确定特异性的作用 蛋白质结构域带来细胞变化。 在第二阶段的工作中，这些研究人员已经获得了 H.幽门螺杆菌基因组和宿主基因阵列的人和小鼠基因。他们 建议使用H。pylori基因芯片检测临床 从明确的流行病学研究中分离出来，以确定 特定的基因或基因组与离散的临床症状相关。 综合征，如溃疡病或恶性肿瘤。建议的主旨 工作将集中在使用DNA阵列来跟踪基因转录， 细菌和宿主基因在感染极化培养的人 上皮细胞他们假设这将允许识别 新的毒力基因所测量的宿主响应的顺序 通过基因转录，建议允许更好地了解宿主 在感染期间被细菌利用的细胞途径。最后 方法称为微阵列转座子标记H. pylori（MATT）， 允许从选择性突变中识别特定类型的突变， 环境，包括受感染的细胞培养物和动物。

DESCRIPTION (Adapted from the Applicant's Abstract): The goal of the proposed research is to understand better the interaction between H. pylori and its human host. H. pylori is the causative agent of gastritis and ulcer disease, and infection is an important risk factor for the development of gastric cancer. In previous studies, these investigators have shown that H. pylori CagA is transported into the host cell, and is then phosphorylated on tyrosine residues by host cell kinase activity. The insertion of CagA into host cells and its subsequent phosphorylation is associated with reorganization of the host cell cytoskeleton, as well as a dramatic change in host cell morphology. The investigators propose to examine the insertion of CagA into host cells and the sequence of events following CagA insertion. In addition, they propose to alter the structure of CagA by mutagenesis to determine the role of specific protein domains in bringing about cellular changes. In a second phase of work, these investigators have obtained DNA arrays of the H. pylori genome and host gene arrays of both human and mouse genes. They propose to use the H. pylori DNA array to examine the genotype of clinical isolates from well-defined epidemiological studies to determine whether particular genes or groups of genes are associated with discrete clinical syndromes like ulcer disease or malignancy. The major thrust of the proposed work will focus on the use of DNA arrays to follow gene transcription of both bacterial and host genes during infection of polarized cultures of human epithelial cells. They hypothesize that this will permit the identification of new classes of virulence genes. The sequence of the host response as measured by gene transcription is suggested to permit better understanding of the host cell pathways that are exploited by the bacteria during infection. Finally, a method called microarray transposon tagged H. pylori (MATT) will be used, which permits the identification of specific classes of mutation from selective environments, including infected cell cultures and animals.