CHARACTERIZATION OF PSEUDOMONAS PHOSPHOLIPASES INVOLVED IN VIRULENCE

参与毒力的假单胞菌磷脂酶的表征

• 批准号: 8168184
• 负责人: MATTHEW J WARGO
• 金额: $ 3.84万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168184
• 关键词: Computer Retrieval of Information on Scientific Projects Database; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Enzymes; Failure; Functional disorder; Funding; Grant; Infection; Institution; Knockout Mice; Lead; Lipase; Lung; Measures; Mechanics; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Phospholipase; Phospholipase C; Pseudomonas; Pseudomonas aeruginosa; Pulmonary Surfactants; Research; Research Personnel; Resources; Respiratory physiology; Role; Source; System; Testing; United States National Institutes of Health; Virulence; Virulence Factors; clinically significant; cystic fibrosis patients; mortality; research study; surfactant; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The most common cause of morbidity and mortality in patients with Cystic Fibrosis (CF) is pulmonary system failure caused by Pseudomonas aeruginosa infection. One potential mechanism of P. aeruginosa damage to the lung is destruction of lung surfactant. Surfactant dysfunction can lead to small airway closure and severely decreased lung function. While the clinical significance of surfactant dysfunction in the CF lung is not fully understood, surfactant dysfunction may result in reduced lung function during exacerbations. We propose that several virulence factors secreted by P. aeruginosa function to degrade surfactant during infection resulting in decreased lung function. Preliminary evidence from a mouse lung infection model shows that P. aeruginosa infected mice show extensive airway closure. Some of this closure is due to the secreted hemolytic phospholipase C, PlcH, but in a plcH deletion strain there remains significant surfactant dysfunction. It is our hypothesis that the secreted lipase encoded by PA4921 is one of the additional mediators of surfactant degradation during P. aeruginosa lung infection. In this study we will verify the predicted enzymatic activity of PA4921 and determine the transcriptional regulatory mechanism governing its induction in pulmonary surfactant. Following the initial characterization, we will examine the role of PA4921 in alteration of lung mechanics in both wild type and Cystic Fibrosis Transmembrane Regulator knock-out (CFTR KO) mice. Lung mechanics, surfactant composition, and surfactant function will be measured during P. aeruginosa infection. Pulmonary instillation of purified PA4921 enzyme will be tested for sufficiency to alter lung mechanics and catalyze surfactant degradation. These experiments will allow us to determine if PA4921 is a potential therapeutic target applicable to CF exacerbations

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 囊性纤维化（CF）患者发病率和死亡率的最常见原因是铜绿假单胞菌感染引起的肺系统衰竭。铜绿假单胞菌对肺损害的一种潜在机制是肺表面活性剂的破坏。表面活性剂功能障碍会导致小气道闭合并严重降低肺功能。尽管尚不完全了解CF肺中表面活性剂功能障碍的临床意义，但表面活性剂功能障碍可能导致肺部功能降低。我们提出，铜绿假单胞菌功能分泌的几个毒力因子在感染过程中降解表面活性剂，从而导致肺功能降低。 小鼠肺部感染模型的初步证据表明，铜绿假单胞菌感染小鼠显示出广泛的气道闭合。其中一些封闭是由于分泌的溶血磷脂酶C，PLCH，但在PLCH缺失菌株中仍然存在明显的表面活性剂功能障碍。我们的假设是，由PA4921编码的分泌脂肪酶是铜绿假单胞菌肺肺肺部感染期间表面活性剂降解的其他介质之一。在这项研究中，我们将验证PA4921的预测酶促活性，并确定控制肺部表面活性剂诱导的转录调节机制。在最初的表征之后，我们将研究PA4921在野生型和囊性纤维化跨膜调节器敲除（CFTR KO）小鼠中的作用。在铜绿假单胞菌感染期间，将测量肺力学，表面活性剂组成和表面活性剂功能。将测试纯化的PA4921酶的肺滴注，以改变肺部力学并催化表面活性剂降解。这些实验将使我们能够确定PA4921是否是适用于CF恶化的潜在治疗目标