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.
|Hisert, Katherine B; Heltshe, Sonya L; Pope, Christopher et al. (2017) Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections. Am J Respir Crit Care Med 195:1617-1628|
|Adam, Ryan J; Hisert, Katherine B; Dodd, Jonathan D et al. (2016) Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities. JCI Insight 1:e86183|
|Kapnadak, Siddhartha G; Hisert, Katherine B; Pottinger, Paul S et al. (2016) Infection control strategies that successfully controlled an outbreak of Mycobacterium abscessus at a cystic fibrosis center. Am J Infect Control 44:154-9|
|Hmelo, Laura R; Borlee, Bradley R; Almblad, Henrik et al. (2015) Precision-engineering the Pseudomonas aeruginosa genome with two-step allelic exchange. Nat Protoc 10:1820-41|
|Wu, Xia; Held, Kiara; Zheng, Chunxiang et al. (2015) Dynamic Proteome Response of Pseudomonas aeruginosa to Tobramycin Antibiotic Treatment. Mol Cell Proteomics 14:2126-37|
|Jorth, Peter; Staudinger, Benjamin J; Wu, Xia et al. (2015) Regional Isolation Drives Bacterial Diversification within Cystic Fibrosis Lungs. Cell Host Microbe 18:307-19|
|Navare, Arti T; Chavez, Juan D; Zheng, Chunxiang et al. (2015) Probing the protein interaction network of Pseudomonas aeruginosa cells by chemical cross-linking mass spectrometry. Structure 23:762-73|
|Secor, Patrick R; Sweere, Johanna M; Michaels, Lia A et al. (2015) Filamentous Bacteriophage Promote Biofilm Assembly and Function. Cell Host Microbe 18:549-59|
|Schweppe, Devin K; Harding, Christopher; Chavez, Juan D et al. (2015) Host-Microbe Protein Interactions during Bacterial Infection. Chem Biol 22:1521-1530|
|Lee, Samuel A; Gallagher, Larry A; Thongdee, Metawee et al. (2015) General and condition-specific essential functions of Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 112:5189-94|
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