Transcriptional Regulation in Helicobacter pylori during Infection

描述(申请人提供)：幽门螺杆菌(H.Pylori)是一种感染约三分之一美国人口和一半世界人口的胃的细菌，可能是最常见的人类细菌感染。为了做到这一点，幽门螺杆菌通过复杂的机制克服了胃部非常低的pH环境。了解幽门螺杆菌对低pH的适应具有重要的科学意义和医学意义。为此，我们将研究调节幽门螺杆菌中pH和胃细胞接触相关基因表达的蛋白质。我们重点研究了两种新的序列特异性DNA结合蛋白。HP0222及其同系物HP0564，我们在结构和生化研究的基础上确定了它们的功能。HP0222在中性条件下适度转录，但在酸性pH培养或与胃细胞接触时上调。我们推测HP0222和HP0564是在幽门螺杆菌毒力中起作用的转录调节因子。我们建议寻找这些蛋白质识别的DNA序列，并确定它们对幽门螺杆菌基因转录的影响。我们将追求三个特定的目标：1.HP0222和HP0564共同识别的DNA序列；2.HP0222和HP0564的结构与DNA结合；3.HP0222和HP0564在发病机制中的作用。完成的AIMS将确定一组在幽门螺杆菌致病过程中重要的基因和新的调节机制。受HP0222和HP0564调控的基因将成为未来基因破坏实验的候选基因。 幽门螺杆菌是一种感染约三分之一美国人口和一半世界人口胃的细菌，是人类最常见的细菌感染。它与十二指肠溃疡、胃炎、胃溃疡、胃癌和胃淋巴瘤等常见和严重的胃肠道疾病有关。这项研究的结果将有助于设计新的和特定的治疗方法来根除幽门螺杆菌，而不需要诉诸于针对普遍共享的生化途径的强烈的副作用诱导的抗生素。

DESCRIPTION (provided by applicant): Helicobacter pylori (H. pylori) is a bacterium that infects the stomachs of around one third of the US population and half of the world population, and is probably the most common human bacterial infection. To accomplish this, H. pylori overcomes the very low pH environment of the stomach via complex mechanisms. Understanding H. pylori adaptation to low pH will have great scientific and medical significance. Towards this end, we will study proteins that regulate pH and gastric cell contact-associated gene expression in H. pylori. We focus on two novel sequence-specific DNA binding proteins. HP0222 and its homolog HP0564, whose functions we established based on our structural and biochemical studies. HP0222 is moderately transcribed under neutral conditions, but becomes up regulated in H. pylori cultured at acidic pH or in contact with gastric cells. We hypothesize that HP0222 and HP0564 are transcriptional regulators that play a role in H. pylori virulence. We propose to find the DNA sequences recognized by these proteins and to determine their effects on the transcription of H. pylori genes. We will pursue three specific aims: 1. consensus DNA sequences recognized by HP0222 and HP0564, 2. structures of HP0222 and HP0564 bound to DNA, 3. HP0222 and HP0564 role in pathogenesis. Completed aims will identify a set of genes and a novel regulatory mechanism important in H. pylori pathogenesis. Genes regulated by HP0222 and HP0564 will be candidates for future gene disruption experiments. Helicobacter pylori is a bacterium that infects the stomachs of around one third of the US population and half of the world population, and is the most common human bacterial infection. It is causatively linked with both common and severe gastrointestinal diseases like duodenal ulcer, gastritis, gastric ulcer, gastric carcinoma and gastric lymphoma. Results of this research will help design novel and specific treatments to eradicate H. pylori without resorting to potent side effect- inducing antibiotics that target universally shared biochemical pathways.