Studies on bacterial populations and therapeutics for CF lung infections

 描述(申请人提供)：这份K24课程的目标是为辛格博士提供工资支持，让他能够将40%的时间花在指导肺部和重症护理研究员、初级教员和其他以患者为导向的慢性呼吸道感染研究方面的实习生。这项提议将使辛格博士能够扩大他的翻译研究计划，将研究员和初级教员纳入该计划，并提供受保护的时间，以便能够指导更多的MD研究员。该提案还提供了时间和基础设施，帮助辛格提高自己的指导技能。所描述的两个研究项目涉及与患者的面对面互动项目1利用初步发现表明，感染铜绿假单胞菌菌株进化为在CF肺内产生遗传多样性但克隆相关的种群，并且随着患者接受抗生素治疗，亚群的相对丰度发生变化。这一点很重要，因为在治疗过程中增加的亚群具有使他们能够在体内抵抗治疗的表型，而那些减少的亚群缺乏抵抗功能。研究这些亚群使我们能够测试关于使细菌在慢性感染中耐受抗生素的机制的新假设。项目2利用的初步发现表明，上呼吸道污染可能会扰乱基于DNA的肺微生物区系测量。准确识别引起CF感染的细菌是CF感染研究中最重要的任务之一。我们建议使用新的“2-Scope方法”和先进的分析方法来检验假设，即使用基于DNA的方法从CF儿童的上呼吸道样本中鉴定出的一些分类群是口咽部污染物，或者来自非活细胞。

 DESCRIPTION (provided by applicant): The goal of this K24 is to provide salary support for Dr. Singh to allow him to spend 40% of his time mentoring pulmonary and critical care fellows, junior faculty and other trainees in patient-oriented research on chronic airway infections. This proposal will enable Dr. Singh to expand his translational research program, integrate fellows and junior faculty in to the program, and provide protected time so that the can mentor additional MD fellows. The proposal also provides time and infrastructure to help Dr. Singh enhance his own mentoring skills. The two research projects described involve face-to-face interactions with patients Project 1 exploits preliminary findings which show that infecting P. aeruginosa strains evolve to produce genetically diverse but clonally-related populations within CF lungs, and that the relative abundance of subpopulations change as patients are treated with antibiotics. This is important because subpopulations that increase during treatment have phenotypes that enable them to resist treatment in vivo, while those that decrease lack resistance functions. Studying these subpopulations enable us to test novel hypotheses about the mechanisms enabling bacteria to withstand antibiotics in chronic infections. Project 2 exploits preliminary findings that show that upper airway contamination may confound DNA-based measurements of lung microbiota. Accurately identifying the bacteria causing CF infections is among the most important tasks in CF infection research. We propose using the novel "2-scope method", along with advanced analytic methods, to test the hypotheses that some of the taxa identified in upper airway samples from CF children using DNA-based methods are oropharyngeal contaminants, or are derived from non viable cells.