The goals of this project are to further the training of Bryan Williams MD PhD as a physician-scientist and advance the field of chronic lung infections. Dr. Williams is a board certified pulmonary/critical care physician who is interested in bacterial infections of the lung, in particular those that persist after antibiotic treatment. He has studied microbiology and lung inflammation in his prior training and has recently been recruited to the University of Minnesota to bridge the outstanding basic science occurring there with the clinical pulmonary research, particularly with respect to cystic fibrosis. Dr. Williams'educational objectives include expanding his knowledge of bacterial and human inflammatory physiology, applying a """"""""systems biology"""""""" approach to bacteria/human interactions, and managing a comprehensive research program with multiple projects and trainees. Dr. Williams has assembled a team of mentors and a research advisory committee to help guide him through his training. The training plan includes regular meetings with mentors, didactic coursework, presentation at national meetings, instruction in education of trainees, manuscript preparation, and a research project. The research project is a continuation of one he created while a post-doctoral fellow in the lab of Dr. Timothy Blackwell at Vanderbilt. This project studies the influences of the metabolism of a breakdown product of arginine called agmatine which he has learned is found in the lungs of patients with chronic infections and appears capable of triggering an inflammatory response. He has also learned that agmatine is important in helping a particular pathogen, Pseudomonas aeruginosa, grow in a manner that helps it survive better in the lung. While each of these findings may be separate lines of research, he is proposing to combine them to better understand the host-pathogen dynamic in the lungs as it actually happens during chronic infections. This project will advance our understanding of bacterial survival in the lung and immune regulation during bacterial infections. It may lead to new therapeutic strategies against bacteria or immune modulation which may improve the lung function, and thus lifespan of patients with these diseases. The training of Dr. Williams as an independent physician scientist will advance the mission of the NIH by creating a scientist that will conduct clinically relevant research, including translational research involving the patients he cares for.

Public Health Relevance

This proposal is designed to train Bryan Williams MD PhD to be a physician scientist in the field of pulmonary infections. His training will result in the creation of a new scientist performing clinically relevant basic science research that may result in new therapies for patients with lung infections.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1)
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Tigno, Xenia
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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Pragman, Alexa A; Berger, John P; Williams, Bryan J (2016) Understanding persistent bacterial lung infections: clinical implications informed by the biology of the microbiota and biofilms. Clin Pulm Med 23:57-66
Dalluge, Joseph J; McCurtain, Jennifer L; Gilbertsen, Adam J et al. (2015) Determination of agmatine using isotope dilution UPLC-tandem mass spectrometry: application to the characterization of the arginine decarboxylase pathway in Pseudomonas aeruginosa. Anal Bioanal Chem 407:5513-9
Gilbertsen, Adam; Williams, Bryan (2014) Development of a Pseudomonas aeruginosa Agmatine Biosensor. Biosensors (Basel) 4:387-402
Paulson, Nick B; Gilbertsen, Adam J; Dalluge, Joseph J et al. (2014) The arginine decarboxylase pathways of host and pathogen interact to impact inflammatory pathways in the lung. PLoS One 9:e111441
Williams, Bryan J; Du, Rui-Hong; Calcutt, M Wade et al. (2010) Discovery of an operon that participates in agmatine metabolism and regulates biofilm formation in Pseudomonas aeruginosa. Mol Microbiol 76:104-19
Williams, Bryan J; Dehnbostel, Joanne; Blackwell, Timothy S (2010) Pseudomonas aeruginosa: host defence in lung diseases. Respirology 15:1037-56