Antibiotic-mediated Adaptation of Pseudomonas aeruginosa

描述（由申请人提供）：本申请描述了一个5年计划，以建立一个独立的职业生涯在学术儿科肺病。候选人的长期目标是开发一个跨学科的研究计划，重点是肺部感染的微生物发病机制，同时保持临床实践，包括候选人的时间的20%。培训环境包括华盛顿大学的Samuel米勒博士的实验室和儿童医院和区域医疗中心的肺科，两者都在西雅图。候选人将通过一个具有基本和翻译组件的项目来扩展他的研究专业知识，并通过高级科学家和临床医生的合作和建议来增强。 细菌生物膜的形成与抗生素耐药性有关。研究得最好的模型系统之一是囊性纤维化（CF）患者的慢性铜绿假单胞菌气道感染。铜绿假单胞菌作为生物膜感染CF气道，并且其在感染期间适应CF气道环境。这些适应影响细菌对抗生素的反应。初步数据表明，铜绿假单胞菌对抗生素妥布霉素的亚抑制浓度有特异性反应，生物膜形成增加。妥布霉素诱导的生物膜对进一步的抗生素挑战更具抗性。初步证据表明，两个细胞信号系统的作用，群体感应和环二鸟苷酸途径，在妥布霉素的反应。已发表的数据导致以下假设：CF铜绿假单胞菌分离株对妥布霉素的反应不同，对肺部疾病进展的影响也不同。我们建议使用现有资源确定铜绿假单胞菌实验室菌株对妥布霉素生物膜反应的分子机制（具体目标1）。然后通过检查CF患者的存档临床分离株以及铜绿假单胞菌的环境菌株来确定该应答的临床相关性（特定目的2）。该项目的最终目标是确定新的治疗靶点，以抑制抗生素耐药性的发展，并帮助根除慢性感染。本提案中的技术和环境是为儿童肺部感染研究职业生涯做准备的理想选择。

DESCRIPTION (provided by applicant): This application describes a 5-year plan to establish an independent career in academic pediatric pulmonology. The candidate's long-term goal is to develop an interdisciplinary research program focusing on microbial pathogenesis in lung infections while maintaining a clinical practice encompassing 20% of the candidate's time. The training environment consists of the laboratory of Dr. Samuel Miller at the University of Washington and the Pulmonary Division at Children's Hospital & Regional Medical Center, both in Seattle. The candidate will expand his research expertise through a project with basic and translational components, augmented by collaboration and advising from senior scientists and clinicians. The formation of bacterial biofilms is associated with antibiotic resistance. One of the best-studied model systems is the chronic Pseudomonas aeruginosa airway infection in people with cystic fibrosis (CF). P. aeruginosa infects CF airways as a biofilm, and it adapts to the CF airway environment during infection. These adaptations affect bacterial responses to antibiotics. Preliminary data demonstrate that P. aeruginosa responds specifically to subinhibitory concentrations of the antibiotic tobramycin with increased biofilm formation. Tobramycin-induced biofilms are more resistant to further antibiotic challenge. Preliminary evidence suggests a role for two cell signaling systems, quorum sensing and the cyclic diguanylate pathway, in the response to tobramycin. Published data led to the hypothesis that responses to tobramycin vary among CF P. aeruginosa isolates, with variable effects on progression of lung disease. We propose to determine the molecular mechanism of the biofilm response of a laboratory strain of P. aeruginosa to tobramycin using available resources (Specific Aim 1). The clinical relevance of this response will then be determined by examining archived clinical isolates from CF patients, as well as environmental strains of P. aeruginosa (Specific Aim 2). The ultimate goal of this project is to identify novel therapeutic targets to inhibit the development of antibiotic resistance, and to aid eradication of chronic infections. The techniques and environments in this proposal are ideal for preparing for a career in the study of lung infections in children.