Studies on bacteriophages in respiratory diseases

项目摘要 Bollyky博士是一名职业生涯中期的调查员，他开发了一个成功的转化研究项目 主要研究噬菌体--感染细菌的病毒--以及细菌性伤口和呼吸道感染。他也是 一个高生产力的研究导师，担任主任的医生，科学家培训计划的 医学住院医师计划，以及培训众多的居民，研究员，和医学生在他自己的实验室。 这个K24的目标是为Bollyky博士提供受保护的时间来发展他以患者为导向的研究 计划和指导额外的临床研究员，初级教师和其他学员在以病人为导向的研究。的 提案还提供了专门的时间和资源，以帮助Bollyky博士提高自己的指导技能， 从咨询委员会获得科学和职业指导，提高他在疫苗学方面的技能， 微生物学，并扩大他在人类临床研究的知识和技术技能。 这项工作的科学重点是噬菌体-感染细菌的病毒-以及它们对细菌的影响。 感染.噬菌体在人体中大量存在，但它们对人类健康的影响在很大程度上是未知的。 Bollyky实验室最近报告说，由主要细菌病原体假单胞菌产生的细菌 铜绿假单胞菌（Pa）促进慢性Pa感染。特别是，他们已经确定了一种新的机制， 由Pa产生丝状Pf β通过作为抗生素耐受性的结构元件而发挥作用， PA生物膜-细菌和聚合物的粘液社区，允许细菌在气道和其他 表面。Pf生物膜组织宿主和微生物聚合物的方式，产生一个强大的生物膜， 抗生素的渗透，导致抗生素耐药性。他们的团队最近发表了Pf 与囊性纤维化（CF）患者的抗生素耐药性升高有关， 痰液粘稠，慢性肺部感染。 可能通过靶向Pf β来保护免受Pa感染。Bollyky实验室最近开发了 一种靶向Pf β的疫苗，以预防Pa感染。然而，目前还不清楚抗Pf抗体是否 这些都是自然发生的，以及这些是否对Pa感染有保护作用。 在这里，Bollyky博士将测试Pf β导致抗生素耐药性和慢性炎症的假设。 感染，而Pf抗体对此提供保护。在目标1中，他们将定义Pfizer如何有助于抗生素 Pa生物膜的耐受性。在目标2中，他们将定义Pf抗体如何保护免受Pa感染。最后，在Aim 他们将确定Pf和抗Pf噬菌体抗体是否影响CF患者的临床结果。 总之，这些研究将产生针对Pa生物膜的新的治疗靶点和治疗策略 感染和启动多个年轻的医生科学家的职业生涯。保护职业发展时间 和指导将使博士Bollyky扩大范围和影响力，他和他的学员的工作和帮助， 维持和发展NIAID和NHLBI以病人为导向的研究事业。

PROJECT SUMMARY Dr. Bollyky is a mid-career investigator who has developed a successful, translational research program focused on bacteriophages – viruses that infect bacteria - and bacterial wound and airway infections. He is also a highly productive research mentor, serving as a director of the physician-scientist training program for the medical residency program as well as training numerous residents, fellows, and medical students in his own lab. The goal of this K24 is to provide Dr. Bollyky with protected time to grow his patient-oriented research program and mentor additional clinical fellows, junior faculty and other trainees in patient-oriented research. The proposal also provides for dedicated time and resources to help Dr. Bollyky enhance his own mentoring skills, obtain scientific and career guidance from an advisory committee, sharpen his skills in vaccinology and microbiology, and expand his knowledge and technical skills in human clinical studies. The scientific focus of this work is bacteriophages – viruses that infect bacteria – and their impact on bacterial infections. Phages are abundant in the human body but their impact on human health is largely unknown. The Bollyky lab has recently reported that phages produced by the major bacterial pathogen Pseudomonas aeruginosa (Pa) promote chronic Pa infections. In particular, they have identified a novel mechanism by which filamentous Pf phages produced by Pa contribute to antibiotic tolerance by functioning as structural elements in Pa biofilms – slimy communities of bacteria and polymers that allow bacteria to colonize airways and other surfaces. Pf phages organize host and microbial polymers in ways that produce a robust biofilm that resists penetration by antibiotics, leading to antibiotic resistance. Their team recently published that Pf phages are associated with heightened antibiotic resistance in patients with cystic fibrosis (CF), a genetic disease associated with thick, tenacious sputum and chronic lung infections with Pa. It may be possible to protect against Pa infection by targeting Pf phages. The Bollyky Lab recently developed a vaccine that targets Pf phages to prevent Pa infections. However, it is unclear whether antibodies against Pf phages naturally occur and whether these are protective against Pa infection. Here, Dr. Bollyky will test the hypothesis that Pf phages contribute to antibiotic resistance and chronic infections while Pf antibodies protect against this. In Aim 1 they will define how Pf phages contribute to antibiotic tolerance in Pa biofilms. In Aim 2 they will define how Pf antibodies protect against Pa infections. Finally, in Aim 3 they will determine whether Pf and anti-Pf phage antibodies influence clinical outcomes in patients with CF. Together, these studies will give rise to novel therapeutic targets and treatment strategies against Pa biofilm infections and launch the careers of multiple young physician scientists. Protected time for career development and mentoring will allow Dr. Bollyky to broaden the scope and influence of his and his trainees’ work and help to sustain and grow the patient-oriented research enterprise of the NIAID and the NHLBI.