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: 6704638
• 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/6704638
• 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）： 将研究幽门螺杆菌 (Hp) 中多磷酸盐 (polyP) 代谢的控制，幽门螺杆菌是一种与消化性溃疡病和胃癌有关的挑剔微需氧病原体。 PolyP 是由数百个磷酸酯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（例如大肠杆菌、铜绿假单胞菌；与生理学上的 Hp 完全不同）的研究表明，polyP 是抗逆性、运动性和毒力等特性所必需的；聚磷酸 (polyP) 由聚磷酸激酶 (PPK) 产生，并被 PPK 或外切多磷酸酶 (PPX) 消耗。 Hp 是遗传多样性最丰富的细菌物种之一。据推测，Hp 的某些多样性会影响代谢基因研究中可能出现的重要数量表型性状。我们的初步结果表明 (i) ppk1 基因对于某些 Hp 菌株至关重要，但对于其他菌株则不然； (ii) 在不需要 ppk1 的菌株中，ppk1 失活可能会阻碍或损害小鼠的生长。拟议的研究有两个具体目标。第一：更好地了解 ppk1 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，我们将进一步测试推断的 ppk1 在某些 Hp 菌株中的重要性；选择至少部分补偿 ppk1 失活的基因或突变等位基因；并研究外切多磷酸酶 (PPX) 和 PPK1 之间的相互作用。第二：了解体内对 PPK1 或 polyP 的需求是否取决于宿主基因型或生理学，以及 PPK1 是否主要用于建立或维持感染。这些测试将涉及使用炎症反应显着不同（例如 IL-10 和 IL-12 敲除）的适当人 Hp 小鼠品系以及沙鼠（一种更宽容的宿主）进行实验感染。总的来说，拟议的研究将增加对幽门螺杆菌感染机制和相关疾病的了解，或许还会增加对谁应该治疗感染以及如何最有效地治疗的了解。