Regulation of Fatty Acid Biosynthesis and Degradation in Pseudomonas aeruginosa

描述（由申请人提供）：铜绿假单胞菌在肺中复制到非常高细胞密度（HCD），使细菌群体感应并分泌大量毒力毒素，导致囊性纤维化（CF）患者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P. aeruginosa中两种控制毒力的酰基化-同丝氨酸-内酯（AHL）分子的合成，Fad作为营养来源参与囊性纤维化肺中磷脂酰胆碱（PC）的代谢。因此，Fab-和fad -通路通过允许HCD复制和产生两个AHL群体感应分子，对铜绿假单胞菌的发病机制至关重要。这两种途径的调控在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P. aeruginosa中协调反向调节，通过上调一条途径而下调另一条途径。基于这一工作假设，我们建议：i)识别和表征控制fabAB和对PC代谢重要的fadba操作子之一的调节因子，ii)通过微阵列实验建立在同一调节因子中调节的其他Fad或Fab相关基因。在遗传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的关键生理和控制过程的关键。此外，它将有助于鉴定在CF肺中可能有助于营养利用的相同调控中的其他fad基因。铜绿假单胞菌（P. aeruginosa）是一种新出现和再出现的传染性病原体，对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，并导致数十万CF患者（主要是儿童）长期痛苦和高死亡率。因此，我们期望这些研究将有助于创新方法，改进治疗，延长慢性肺部感染CF患者的生命。

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.