Studies on bacteriophages in respiratory diseases

噬菌体在呼吸系统疾病中的研究

基本信息

批准号：
10669271
负责人：
Paul L Bollky
金额：
$ 16.44万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-20 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669271
关键词：
Advisory Committees Air Antibiotic Resistance Antibiotics Antibodies Antibody-mediated protection Antimicrobial Resistance Bacteria Bacterial Infections Bacteriophages Binding Chronic Clinical Clinical Research Communities Cystic Fibrosis Cytolysis Dedications Development Diffusion Elements Epithelial Cells Faculty Family suidae Genetic Diseases Genomics Goals Growth Health Human Human body Immunization Individual Infection Inhalation Knowledge Liquid substance Longitudinal cohort Lung infections Mediating Medical Medical Residency Medical Students Mentors Microbial Biofilms Microbiology Modeling Mus National Heart, Lung, and Blood Institute National Institute of Allergy and Infectious Disease Outcome Patients Penetration Phagocytosis Physicians Polymers Production Productivity Pseudomonas aeruginosa Pseudomonas aeruginosa infection Publishing Reporting Research Research Personnel Resources Respiratory Disease Respiratory Tract Infections Role Scientist Sputum Surface Technical Expertise Testing Thick Time Training Translational Research Virus Vocational Guidance Work Wound Infection antibiotic tolerance career career development chronic infection cystic fibrosis patients emerging antimicrobial resistance human subject microbial molecular sequence database monocyte natural antibodies new therapeutic target novel pathogenic bacteria patient oriented research physician-scientist training program prevent programs resistance gene respiratory colonization response skills translational research program treatment strategy vaccine development vaccinology wound

项目摘要

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.

项目概要 Bollyky 博士是一位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他还专注于噬菌体（感染细菌的病毒）以及细菌伤口和呼吸道感染。一位高产的研究导师，担任医学科学家培训项目的主任住院医师计划以及在他自己的实验室中培训众多住院医师、研究员和医学生。 K24 的目标是为 Bollyky 博士提供受保护的时间来开展以患者为导向的研究计划并指导其他临床研究员、初级教师和其他受训人员进行以患者为导向的研究。提案还提供了专门的时间和资源来帮助 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，提高疫苗学技能和微生物学，并扩展他在人类临床研究方面的知识和技术技能。这项工作的科学重点是噬菌体（感染细菌的病毒）及其对细菌的影响噬菌体在人体内大量存在，但其对人类健康的影响很大程度上未知。 Bollyky 实验室最近报告称，主要细菌病原体假单胞菌产生的噬菌体铜绿假单胞菌 (Pa) 促进慢性 Pa 感染，特别是，他们发现了一种新的机制。 Pa 产生的丝状 Pf 噬菌体通过充当抗生素耐受性的结构元件而有助于抗生素耐受性。 Pa 生物膜——由细菌和聚合物组成的粘液群落，使细菌能够在呼吸道和其他部位定殖 Pf噬菌体以产生坚固的抵抗生物膜的方式组织宿主和微生物聚合物。他们的团队最近发表文章称，Pf 噬菌体是抗生素的渗透，导致抗生素耐药性。与囊性纤维化 (CF) 患者的哮喘抗生素耐药性相关，囊性纤维化是一种与遗传病相关的疾病伴有粘稠、粘稠痰液和 Pa 慢性肺部感染。 Bollyky 实验室最近开发的靶向 Pf 噬菌体可能可以防止 Pa 感染。一种针对 Pf 噬菌体以预防 Pa 感染的疫苗，但尚不清楚是否存在针对 Pf 的抗体。噬菌体自然存在，以及它们是否能预防 Pa 感染。在此，Bollyky 博士将检验 Pf 噬菌体导致抗生素耐药性和慢性病的假设。在目标 1 中，他们将定义 Pf 噬菌体如何发挥抗生素作用。在目标 2 中，他们将定义 Pf 抗体如何预防 Pa 感染。 3 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 生物膜的新治疗靶点和治疗策略感染并启动多名年轻医师科学家的职业发展时间。指导将使 Bollyky 博士能够扩大他和他的学员的工作范围和影响力，并帮助维持和发展 NIAID 和 NHLBI 以患者为中心的研究事业。