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（息肉）代谢的控制，这是一种涉及消化性溃疡疾病和胃癌的挑剔的微型病原体。息肉是数百种由高能磷酸氢化盐键连接的磷酸盐残基的长链聚合物。使用快速生长的物种（例如，大肠杆菌，铜绿假单胞菌；与生理学中的HP完全不同）的研究表明，诸如抗压力，运动性和毒力等性状需要息肉。该息肉是由多磷酸激酶（PPK）制成的，并由PPK或外磷酸酶（PPX）消耗。 HP是细菌种类最多样化的物种之一。假设惠普的某些多样性会影响代谢基因研究中可能看到的重要定量表型特征。我们的最初结果表明（i）PPK1Gene对于某些HP菌株，而不是其他菌株至关重要； （ii）在PPK1可分配的菌株中，PPK1失活会阻止或损害小鼠的生长。拟议的研究有两个具体的目标。首先：更好地理解ppk1和息肉在HP中的作用，以及在这些角色中HP菌株之间的多样性。在这里，我们将进一步测试某些HP菌株中PPK1的推断重要性。选择至少部分补偿PPK1失活的基因或突变等位基因；并研究外磷酸酶（PPX）和PPK1之间的相互作用。第二：要了解对体内PPK1或息肉的需求是否取决于宿主的基因型或生理学，以及是否需要PPK1主要建立或维持感染。这些测试将涉及使用适当的人类HP小鼠系的HP菌株的实验感染，这些HP菌株在炎症反应中明显不同（例如IL-10和IL-12敲除），以及更宽松的宿主Gerbils。总的来说，拟议的研究将增加对HP感染机制和相关疾病的理解，也许是谁治疗感染以及这种治疗方法最有效。