Metal-dependent regulation of the H. pylori Cag type IV secretion system

描述（由申请方提供）：幽门螺杆菌是人类胃生态位中主要的定植原核生物。H.幽门螺杆菌感染导致持续的慢性炎症，并且是发生消化性溃疡和胃腺癌的强危险因素。腺癌的发展取决于多种因素，包括宿主遗传学、饮食和细菌因素。细菌致病的一个特殊特征是H。pylori cag致病岛（cag派），其编码负责将致癌蛋白CagA递送到胃上皮细胞中的IV型分泌系统（T4 SS）。T4 SS装置跨越两个细菌膜，并且包括被称为T4 SS菌毛的细胞外细胞器。这种细胞器被认为是负责损害真核细胞膜和CagA易位。虽然T4 SS在H.幽门螺杆菌的发病机制和最终的致癌作用，调节组装这个复杂的分子机器的机制在很大程度上是模糊的。本申请提出了将阐明调节cag T4 SS的机制的实验。具体而言，我们假设T4 SS菌毛的组装受金属（如铁和锌）的可用性调节。我们将利用电子显微镜，定量RT-PCR和分子生物学技术相结合，揭示了复杂的调控网络，管理这个重要的细胞器的生物发生。 公共卫生相关性：幽门螺杆菌是一种细菌，定植在人类的胃，并有助于胃癌和消化性溃疡疾病。这项研究旨在了解这种细菌如何调节cag IV型分泌系统，该系统将致癌效应物转移到宿主细胞中。这些知识可能会导致预防和治疗胃癌和消化性溃疡疾病的新方法。

DESCRIPTION (provided by applicant): Helicobacter pylori is the predominant colonizing prokaryote in the human gastric niche. H. pylori infection results in persistent chronic inflammation, and is a strong risk factor for the development of peptic ulceration and gastric adenocarcinoma. The development of adenocarcinoma is dependent upon a variety of factors, including host genetics, diet, and bacterial factors. One specific feature that contributes to bacterial pathogenesis is the H. pylori cag pathogenicity island (cag PAI), which encodes a type IV secretion system (T4SS) responsible for the delivery of the oncogenic protein CagA into gastric epithelial cells. The T4SS apparatus spans two bacterial membranes and includes an extracellular organelle referred to as the T4SS pilus. This organelle is proposed to be responsible for compromising the eukaryotic membrane and translocation of CagA. Although the T4SS has an important role in H. pylori pathogenesis and ultimately carcinogenesis, the mechanisms that regulate assembly of this complex molecular machine are largely obscure. This application proposes experiments that will elucidate the mechanisms by which the cag T4SS is regulated. Specifically, we hypothesize that assembly of the T4SS pilus is regulated by the availability of metals such as iron and zinc. We will utilize a combination of electron microscopy, quantitative RT-PCR, and molecular biology techniques to shed light upon the complex regulatory networks that govern the biogenesis of this important organelle. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is a bacterium that colonizes the human stomach and contributes to gastric cancer and peptic ulcer disease. This research seeks to understand how this bacterium regulates the cag type IV secretion system, which translocates carcinogenic effectors into host cells. This knowledge may lead to new approaches for the prevention and treatment of stomach cancer and peptic ulcer disease.