Bacteriophage as a predictive biomarker in chronic Pseudomonas airway disease

项目摘要/摘要 尽管在治疗方面取得了重大进展，但肺部疾病仍然主导着临床进程。 囊性纤维化症(CF)患者。所有慢性肺泡炎患者都会发生慢性肺部感染， 铜绿假单胞菌(PA)成为成年期的优势菌。即使在面对 慢性吸入抗生素治疗以肺部PA为靶点，CF患者经历间歇性 肺恶化，肺功能逐渐下降，最终导致呼吸衰竭。 迫切需要新的治疗策略来解决慢性前列腺癌的破坏性影响。 慢性萎缩性胃炎患者的肺。这将使所有CF患者都能充分受益于一种不断发展的治疗方法 景观，以解决他们的CF基因功能缺陷。 我发现在CF患者队列中存在PA丝状(PF)噬菌体 在斯坦福和丹麦。Pf与PA的慢性化和更严重的恶化有关 (Burgener等人，《科学转化医学2019》)。这是第一次演示 噬菌体与人类肺部疾病的关系。这项提议旨在深入研究这些机制 在这些联想的背后。鉴于慢性吸入性抗生素疗法的已知缺点，我 将检验这样一种假设，即在肺内，PF提供抗生素耐受性，并且是预测 选择有效的吸入疗法的指南。第一个目标是利用银行的呼吸道 分离到(1a)，在肺部存在的情况下评估抗生素耐受性，(1b)执行 基因组测序以评估抗生素耐药性基因的存在和(1c)执行进化 研究抗性获得与Pf的关系的实验。第二个目标是评估PF 作为肺部疾病预测生物标记物的(2a)回顾队列评估对 恶化治疗和(2b)进行交叉临床试验以评估PF的不同效果 对肺功能的影响。这项建议得到了令人兴奋和新颖的初步数据的支持，有望提供 Pf作为预测生物标志物指导吸入的理论基础和机制基础 慢性阻塞性肺疾病治疗中的抗生素选择。 这项拟议的研究借鉴了我以前在临床肺部内科和 翻译研究方面日益增长的专业知识。与我的导师和顾问委员会一起，我向大家介绍 一个全面的微生物学教学和技术培训的职业发展计划， 基因组学、临床试验设计和生物统计学。这项培训，以及临床研究和 概述的实验，将使我发展关键的技能，我过渡到一个独立的 翻译研究生涯专注于带来新的治疗方法和治疗策略 CF肺部疾病的变革性治疗。

PROJECT SUMMARY / ABSTRACT Despite major advances in therapy, pulmonary disease continues to dominate the clinical course of patients with cystic fibrosis (CF). All patients with CF develop chronic lung infections, with Pseudomonas aeruginosa (Pa) becoming a predominant organism in adulthood. Even in the face of chronic inhalational antibiotic therapy to target Pa in the lungs, CF patients experience intermittent pulmonary exacerbations with stepwise decline in lung function leading to eventual respiratory failure. Novel treatment strategies are urgently needed to address the damaging effects of chronic Pa in the lungs of CF patients. This will allow for all patients with CF to fully benefit of an evolving therapeutic landscape to address their defective CF gene function. I discovered the presence of the Pa filamentous (Pf) bacteriophage, in cohorts of patients with CF in Stanford and Denmark. Pf was associated with chronicity of Pa and more severe exacerbations (Burgener et al, Science Translational Medicine 2019). This constituted the first demonstration of the involvement of bacteriophage in human lung disease. This proposal aims to delve into the mechanisms behind these associations. Given the known shortcomings of chronic inhalational antibiotic therapy, I will test the hypothesis that in the lung Pf provides antibiotic tolerance and is a predictive biomarker to guide in choosing effective inhalational therapeutics. The first aim utilizes banked respiratory Pa isolates to (1a), assess antibiotic tolerance under conditions present in the lung, (1b) perform whole genome sequencing to assess for presence of antibiotic resistance genes and (1c) perform evolutionary experiments to investigate acquisition of resistance as a function of Pf. The second aim will assess Pf as a lung disease predictive biomarker in (2a) a retrospective cohort evaluating response to exacerbations therapy and (2b) perform a cross-over clinical trial to assess for differential effects of Pf on lung function. This proposal, supported by exciting and novel preliminary data, promises to provide rationale and mechanistic foundation for Pf to be used as a predictive biomarker to guide inhalational antibiotic choices in CF airway disease management. The proposed research draws upon my prior experience in clinical pulmonary medicine and growing expertise in translational research. Along with my mentors and advisory committee, I present a comprehensive career development plan for didactics and technical training in microbiology, genomics, and clinical trial design and biostatistics. This training, along with the clinical studies and experiments outlined, will allow me to develop skills crucial for my transition to an independent translational research career focused on bringing new therapies and treatment strategies for transformative management of CF lung disease.