GENETICS OF POLYPHOSPHATE METABOLISM IN H. PYLORI

幽门螺杆菌中多磷酸盐代谢的遗传学

• 批准号: 6833482
• 负责人: DOUGLAS Eugene BERG
• 金额: $ 7.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833482
• 关键词: Helicobacter; bacterial genetics; enzyme activity; gerbil /jird; host organism interaction; immune response; inflammation; laboratory mouse; microorganism metabolism; other phosphotransferase; phosphorus metabolism; polyphosphates

DESCRIPTION (provided by applicant): The control of polyphosphate (polyP) metabolism will be studied in Helicobacter pylori (Hp), a fastidious microaerobic pathogen implicated in peptic ulcer disease and gastric cancer. PolyP is a long chain polymer of hundreds of phosphate residues linked by high-energy phosphoanydride bonds. Studies using fast growing species (e.g., E. coli, P. aeruginosa; quite unlike Hp in physiology) indicate that polyP is needed for traits such as stress resistance, motility and virulence; and that polyP is made by polyphosphate kinases (PPK), and consumed by PPK or an exopolyphosphatase (PPX). Hp is one of the most genetically diverse of bacterial species. Some of Hp's diversity is postulated to affect important quantitative phenotypic traits that might be seen in studies of metabolic genes. Our initial results indicate that (i) the ppk1gene is essential for some Hp strains, but not others; and (ii) in strains for which ppk1 is dispensable, ppk1 inactivation can block or impair growth in mice. The proposed studies have two specific aims. First: To better understand roles of ppk1 and polyP in Hp, and diversity among Hp strains in these roles. Here we will further test the inferred essentiality of ppk1 in certain Hp strains; select for genes or mutant alleles that at least partially compensate for ppk1 inactivation; and study the interplay between exopolyphosphatase (PPX) and PPK1. Second: To learn if the need for PPK1 or polyP in vivo depends on host genotype or physiology, and if PPK1 is needed primarily to establish, or also to maintain, infection. These tests will involve experimental infections using appropriate human Hp strains of mouse lines that differ markedly in inflammatory responses (e.g., IL-10 and IL-12 knockout), and also gerbils, a more permissive host. Collectively, the proposed studies will increase understanding of Hp infection mechanisms and associated disease, and perhaps of who to treat for infection and how such treatment can be most effective.

描述（由申请人提供）： 将在幽门螺杆菌（Hp）中研究多磷酸盐（polyP）代谢的控制，幽门螺杆菌是一种与消化性溃疡疾病和胃癌有关的苛求微需氧病原体。PolyP是由数百个磷酸残基通过高能磷酸酐键连接的长链聚合物。使用快速生长物种的研究（例如，E.大肠杆菌、铜绿假单胞菌;与生理学中的Hp非常不同）表明，聚P是诸如抗应激性、运动性和毒力等性状所必需的;并且聚P由聚磷酸激酶（PPK）产生，并由PPK或外聚磷酸酶（PPX）消耗。幽门螺杆菌是遗传多样性最丰富的细菌之一。假设Hp的一些多样性影响重要的数量表型性状，可能会在代谢基因的研究中看到。我们的初步结果表明：（i）ppk 1基因对某些Hp菌株是必需的，但对其他菌株不是必需的;（ii）在ppk 1缺失的菌株中，ppk 1失活可阻断或损害小鼠的生长。拟议的研究有两个具体目标。第一，为了更好地了解ppk 1和polyP在Hp中的作用，以及Hp菌株在这些作用中的多样性。在这里，我们将进一步测试ppk 1在某些Hp菌株中的推断的必要性;选择至少部分补偿ppk 1失活的基因或突变等位基因;并研究外多磷酸酶（PPX）和PPK 1之间的相互作用。第二个：了解体内对PPK 1或polyP的需求是否取决于宿主基因型或生理学，以及PPK 1是否主要用于建立或维持感染。这些测试将涉及使用适当的人Hp菌株的小鼠品系的实验感染，所述小鼠品系在炎症反应方面显著不同（例如，IL-10和IL-12敲除），以及沙鼠，一种更宽容的宿主。总的来说，拟议的研究将增加对Hp感染机制和相关疾病的了解，也许还能了解感染的治疗对象以及这种治疗如何才能最有效。