Regulation of Fatty Acid Biosynthesis and Degradation in Pseudomonas aeruginosa

铜绿假单胞菌脂肪酸生物合成和降解的调控

• 批准号: 7498934
• 负责人: Tung T Hoang
• 金额: $ 20.37万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498934
• 关键词: Bacteria; Binding; Cell Density; Chronic; Critical Pathways; Cystic Fibrosis; DNA Binding; DNA Footprint; Data; Enzymes; Event; Fatty Acids; Gene Fusion; Genes; Genetic; Infection; Infectious Agent; Knowledge; Laboratories; Lecithin; Life; Lung; Lung diseases; Maps; Metabolic; Metabolism; Microbial Biofilms; Molecular Genetics; Morbidity - disease rate; Mutagenesis; Nosocomial pneumonia; Nutrient; Operon; Organism; Pathogenesis; Pathway interactions; Physiology; Positioning Attribute; Process; Production; Promoter Regions; Properdin; Pseudomonas aeruginosa; Public Health; Pulmonary Surfactants; Regulation; Regulon; Research; Role; Source; Sputum; System; Toxin; Virulence; Virulence Factors; Work; acylated homoserine lactone; base; children with cystic fibrosis; cystic fibrosis patients; experience; fatty acid biosynthesis; genetic regulatory protein; improved; in vivo; innovation; milliliter; mortality; mutant; pathogen; prevent; promoter; quorum sensing; research study

DESCRIPTION (provided by applicant): Replication of Pseudomonas aeruginosa to very high-cell-density (HCD) in the lung allows the bacteria to quorum-sense and secrete numerous virulence toxins, causing severe and chronic lung infections in cystic fibrosis (CF) patients. Central to these processes are Fatty acid biosythesis (Fab) and fatty acid degradation (Fad). Fab is responsible for the syntheses of two virulence-controlling acylated-homoserine- lactone (AHL) molecules in P. aeruginosa, and Fad contributes to phosphatidylcholine (PC) metabolism in the Cystic Fibrosis lung as a nutrient source. Hence, both Fab- and Fad-pathways are critical for the pathogenesis of P. aeruginosa by allowing HCD replication and producing two AHL quorum-sensing molecules. Regulation of both pathways is largely unknown. The working hypothesis, based on our preliminary data, is that Fab and Fad are coordinately inverse regulated in P. aeruginosa, by up-regulating one pathway and down-regulating the other. Based on this working hypothesis, we propose to: i) identify and characterize the regulator that controls fabAB and one of the fadBA-operons important for PC metabolism and ii) perform microarray experiments to establish other Fad or Fab related genes that are regulated in the same regulon. Identifying this regulatory protein that controls both pathways, at the genetic level, is the key to understanding physiology and control of processes that are critical for the pathogenesis of P. aeruginosa. In addition, it will contribute to the identification of other fad-genes in the same regulon that could contribute to nutrient utilization in the CF lung. P. aeruginosa is an emerging and re-emerging infectious agent that causes serious burdens to public health, because it is a major culprit of hospital-acquired pneumonia and causes prolonged suffering and high mortality to hundreds of thousands of people (mostly children) with CF. Hence, it is expected that these studies will contribute to innovative approaches for improved treatment to extend the lives of CF patients with debilitating chronic lung infections.

描述（由申请人提供）：铜绿假单胞菌在肺部复制到非常高的细胞密度（HCD），使细菌能够感知群体并分泌大量毒力毒素，导致囊性纤维化（CF）患者出现严重和慢性肺部感染。这些过程的核心是脂肪酸生物合成（Fab）和脂肪酸降解（Fad）。 Fab 负责铜绿假单胞菌中两种毒力控制酰化高丝氨酸内酯 (AHL) 分子的合成，Fad 有助于囊性纤维化肺中作为营养源的磷脂酰胆碱 (PC) 代谢。因此，Fab 和 Fad 途径通过允许 HCD 复制并产生两个 AHL 群体感应分子，对于铜绿假单胞菌的发病机制至关重要。这两种途径的调节很大程度上是未知的。基于我们的初步数据，工作假设是 Fab 和 Fad 在铜绿假单胞菌中协同反向调节，通过上调一个途径并下调另一个途径。基于这一工作假设，我们建议：i) 识别和表征控制 fabAB 的调节因子和对 PC 代谢重要的 fadBA 操纵子之一，ii) 进行微阵列实验以建立在相同的调节子。在基因水平上识别这种控制这两种途径的调节蛋白是了解铜绿假单胞菌发病机制关键过程的生理学和控制的关键。此外，它将有助于识别同一调节子中的其他 fad 基因，这些基因可能有助于 CF 肺中的营养利用。铜绿假单胞菌是一种新出现和重新出现的传染原，给公共卫生造成严重负担，因为它是医院获得性肺炎的罪魁祸首，给数十万囊性纤维化患者（主要是儿童）造成长期痛苦和高死亡率。因此，预计这些研究将有助于改进治疗的创新方法，以延长患有慢性肺部感染的囊性纤维化患者的生命。