Bacteriophage as a predictive biomarker in chronic Pseudomonas airway disease

噬菌体作为慢性假单胞菌气道疾病的预测生物标志物

基本信息

批准号：
10723956
负责人：
Elizabeth Bendig Burgener
金额：
$ 19.9万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-22 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723956
关键词：
Acute Address Adult Advisory Committees Airway Disease Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Antimicrobial susceptibility Aztreonam Bacterial Chromosomes Bacteriophages Biological Markers Biological Testing Biology Biometry Bronchiectasis Caring Chronic Clinical Clinical Research Clinical Trials Clinical Trials Design Cystic Fibrosis Cystic Fibrosis sputum Data Denmark Development Development Plans Disease Disease Management Environment Evolution Foundations Future Genomics Growth Human Impairment In Vitro Infection Inhalation Inovirus Longitudinal cohort Lung Lung diseases Lung infections Measures Mediating Mentors Microbial Biofilms Microbiology Minimum Inhibitory Concentration measurement Nonlytic Organism Patient Care Patients Phenotype Phylogeny Physicians Polysaccharides Population Prophages Pseudomonas Pseudomonas aeruginosa Pseudomonas aeruginosa infection Publishing Pulmonary Cystic Fibrosis Pulmonology Recurrence Research Resistance Respiratory Disease Respiratory Failure Respiratory Tract Infections Retrospective cohort Sampling Scientist Serial Passage Sputum Testing Therapeutic Time Tobramycin Tracheostomy procedure Training Translational Research Virion Virus Integration antibiotic tolerance biobank career career development chronic infection clinical care cohort cystic fibrosis airway cystic fibrosis infection cystic fibrosis patients emerging antibiotic resistance experience experimental study gene function genome sequencing improved outcome in vivo insight mucoid novel novel therapeutics pathogen personalized approach predicting response predictive marker prospective pulmonary function resistance gene respiratory response response biomarker skills translational medicine treatment strategy whole genome

项目摘要

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.

项目概要/摘要尽管治疗取得了重大进展，但肺部疾病仍然在临床过程中占主导地位囊性纤维化（CF）患者。所有 CF 患者都会出现慢性肺部感染，铜绿假单胞菌 (Pa) 成为成年期的主要微生物。即使面对慢性吸入性抗生素治疗以肺部 Pa 为目标，CF 患者会出现间歇性症状肺部病情加重，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 Pa 的破坏性影响 CF患者的肺部。这将使所有 CF 患者能够充分受益于不断发展的治疗方法景观来解决其有缺陷的 CF 基因功能。我发现 CF 患者群体中存在 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）。这是该项目的首次演示噬菌体参与人类肺部疾病。该提案旨在深入研究机制这些协会的背后。鉴于慢性吸入抗生素治疗的已知缺点，我将检验以下假设：Pf 在肺部提供抗生素耐受性，并且是一种预测性生物标志物指导选择有效的吸入疗法。第一个目标利用储存呼吸 Pa 分离到（1a），评估肺部条件下的抗生素耐受性，（1b）执行整体基因组测序以评估抗生素抗性基因的存在，并 (1c) 进行进化实验研究电阻的获取作为 Pf 的函数。第二个目标将评估 Pf 作为（2a）回顾性队列中的肺部疾病预测生物标志物，评估对急性加重治疗并 (2b) 进行交叉临床试验以评估 Pf 的差异效应关于肺功能。该提案得到了令人兴奋且新颖的初步数据的支持，有望提供 Pf 用作指导吸入的预测生物标志物的基本原理和机制基础 CF 气道疾病管理中的抗生素选择。拟议的研究借鉴了我之前在临床肺医学方面的经验和不断增长的转化研究专业知识。我与我的导师和咨询委员会一起提出微生物学教学和技术培训的全面职业发展计划，基因组学、临床试验设计和生物统计学。此次培训以及临床研究和概述的实验将使我能够发展对我过渡到独立的至关重要的技能转化研究事业的重点是为患者带来新的疗法和治疗策略 CF 肺部疾病的变革性管理。