Studies on bacterial populations and new therapeutics for CF lung infections

细菌种群和 CF 肺部感染新疗法的研究

• 批准号: 8127844
• 负责人: PRADEEP k SINGH
• 金额: $ 17.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127844
• 关键词: Affect; Animal Model; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Bacteria; Biological; Chemicals; Chronic; Clinical Research; Communities; Critical Care; Cystic Fibrosis; Data; Drug Kinetics; Environment; Equus caballus; Faculty; Funding; Gallium; Genetic Variation; Genomics; Goals; Growth; Host Defense; Human; Infection; Infusion procedures; Interdisciplinary Study; Iron; Laboratory Study; Link; Lung; Measures; Mentors; Metabolism; Metals; Microbial Biofilms; Microbiology; Modeling; Multi-Drug Resistance; Organism; Pathogenesis; Patients; Physicians; Population; Process; Pseudomonas aeruginosa; Research; Research Infrastructure; Research Personnel; Research Project Grants; Research Support; Research Training; Resistance; Resources; Scientist; Stress; System; Testing; Therapeutic; Time; Training; Translational Research; Wages; Work; combat; cystic fibrosis patients; in vivo; killings; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; patient oriented research; pre-clinical; preclinical study; programs; research study; resistant strain; safety study; skills; uptake

DESCRIPTION (provided by applicant): The goal of this K24 proposal is to provide salary support for Dr Singh to allow him to spend 50% of his time mentoring pulmonary and critical care fellows, junior faculty and other trainees in patient-oriented research on chronic airway infections. This proposal also will allow Dr Singh to expand his translational research program, and integrate fellows and junior faculty in to the program. Finally, the proposal provides time and infrastructure to help Dr Singh enhance his mentoring skills. The two research projects described are ideal for training physician-scientists in translational research as they involve face-to-face interaction with patients, and laboratory studies in microbiology and genomics. They will also increase our understanding of infection pathogenesis in cystic fibrosis (CF) and other chronic infections, and advance a new therapeutic approach. In Project 1, we examine a novel anti-infective approach that uses the metal gallium (Ga) to disrupt bacterial iron (Fe) metabolism. Due to its chemical similarity to Fe, Ga can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. Our data shows that Ga kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and effectively treats 3 different model infections. We propose preclinical laboratory studies to further investigate Ga's activity, and a pharmacokinetic and safety study of IV Ga in subjects with CF. In Project 2, we study genetic diversity in P. aeruginosa populations infecting CF patients. In preliminary studies, we found that infecting P. aeruginosa strains evolve to produce a genetically diverse bacterial population within the host. This is important because diversity can markedly increase the stress resistance of biological communities, and their ability to exploit available resources. If these principles apply to bacterial populations infecting humans, diversity may enhance ability of the bacteria to persist in the face of host defenses and antibiotic treatment. We will measure the genetic diversity of P. aeruginosa populations infecting CF patients, and propose experiments to understand how this diversity affects infectious exacerbations and the efficacy of antibiotic treatment. The goal of this K24 is to provide salary support for Dr Singh to allow him to spend 50% 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 allow Dr Singh to expand his translational research program, integrate fellows and junior faculty in to the program, and provide protected time so that he can mentor additional MD fellows. The project also supports research on the pathogenesis of CF infections, and on a new therapeutic approach.

描述（由申请人提供）： 这项 K24 提案的目标是为 Singh 博士提供薪资支持，使他能够花 50% 的时间指导肺部和重症监护研究员、初级教员和其他受训人员进行以患者为导向的慢性气道感染研究。该提案还将使辛格博士能够扩大他的转化研究计划，并将研究员和初级教师纳入该计划。最后，该提案提供了时间和基础设施来帮助辛格博士提高他的指导技能。所描述的两个研究项目非常适合培训医师科学家进行转化研究，因为它们涉及与患者面对面的互动以及微生物学和基因组学的实验室研究。它们还将增加我们对囊性纤维化（CF）和其他慢性感染的感染发病机制的了解，并推进新的治疗方法。在项目 1 中，我们研究了一种新颖的抗感染方法，该方法使用金属镓 (Ga) 来破坏细菌铁 (Fe) 代谢。由于其化学性质与 Fe 相似，Ga 可以在许多生物系统中替代 Fe 并抑制 Fe 依赖性过程。我们的数据显示，Ga 可杀死机会性病原体铜绿假单胞菌（包括抗生素耐药菌株），对生物膜具有活性，并能有效治疗 3 种不同的感染模型。我们建议进行临床前实验室研究以进一步研究 Ga 的活性，并进行 IV Ga 在 CF 受试者中的药代动力学和安全性研究。在项目 2 中，我们研究了感染 CF 患者的铜绿假单胞菌群体的遗传多样性。在初步研究中，我们发现感染铜绿假单胞菌菌株在宿主体内进化产生遗传多样性的细菌群体。这很重要，因为多样性可以显着提高生物群落的抗压能力及其利用可用资源的能力。如果这些原则适用于感染人类的​​细菌群体，多样性可能会增强细菌在面对宿主防御和抗生素治疗时持续存在的能力。我们将测量感染 CF 患者的铜绿假单胞菌群体的遗传多样性，并提出实验来了解这种多样性如何影响感染恶化和抗生素治疗的功效。 此次K24的目标是为Singh博士提供薪资支持，让他可以花掉自己50%的钱 花时间指导肺部和重症监护研究员、初级教员和其他学员以患者为中心 慢性气道感染的研究。该提案将使辛格博士能够扩大他的转化研究计划，将研究员和初级教师纳入该计划，并提供受保护的时间，以便他可以指导其他医学博士研究员。该项目还支持 CF 感染发病机制和新治疗方法的研究。