Department of Comparative Medicine School of Medicine University of Washington Seattle, WA 98195 email: cfrevert@uw.edu

Veterinary Training : Iowa State University School of Veterinary Medicine

Residency: Tufts University School of Veterinary Medicine, Large Animal Internal Medicine Residency

Graduate School : Harvard School of Public Health, Doctor of Science Degree (Sc.D.) in Physiology and Cell Biology

Faculty Appointments :

1997 - Research Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine/Department of Medicine

2002 - Research Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine/Department of Medicine

2008 - Research Associate Professor Department of Comparative Medicine

Research Interests:

With the evolution of multidrug-resistant pathogens, an increase in zoonotic lung infections, the threat of bioterrorism, an aging population, and an increasingly urban, yet globally mobile society, we are more vulnerable to lung infection today than at any time in our history. The early response of the immune system to viral and bacterial infections is mediated by the innate immune system. Our laboratory studies this early response with the goal to better understand the mechanisms that are responsible for the successful clearance of bacteria and viruses from the lungs. An important focus of my laboratory is to determine the role that glycosaminoglycans and proteoglycans play in the innate immune response to lung infection. Glycosaminoglycans are linear polymers of repeating disaccharides with a high negative charge. Examples of glycosaminoglycans in lungs include heparin, heparan sulfate, chondroitin sulfate, and hyalurnonan. Proteoglycans are a family of molecules containing a core protein and one or more covalently attached glycosaminoglycan side chains (Figure 1). Initially work in my laboratory focused on the role of glycosaminoglycans in controlling chemokine function and leukocyte migration and activation in the lungs. More recent works has focused on two areas. The first area of research is the role of Toll-like receptors in regulating the expression of proteoglycans during lung infection. The second area of research is to determine the role of proteoglycans such as versican and syndecan-4 and the glycosaminoglycan, hyaluronan, on the recruitment and activation of leukocytes in response to lung infection.

Figure 1 : Heparan sulfate and chondroitin sulfate proteoglycans found in the extracellular matrix of healthy lungs. Versican (green) and hyaluronan (yellow, HA) form large molecular weight complexes that are increased in infected lungs. Current work focuses on understanding the role of versican-HA complexes in modulating pulmonary inflammation. The drawing by Mark Baskin was p ublished in, Frevert, C. and T.N. Wight, Matrix Proteoglycans, in The Encyclopedia of Respiratory Medicine, G.J. Laurent, Editor. 2006, Elsevier: London , U.K. p. 184-187.

Comparative Pathology Program :

Veterinarians have a high level of training and understanding of whole animal biology and cross-species disease differences. Their specialty training in molecular disease pathogenesis and interpretation of lesions results in the improved development and characterization of animal models. Central to this is the need to integrate mouse pathology with genomics, proteonomics and metabolonomics to better understand complex disease processes and to translate these findings to human diseases. In order to integrate the ‘Omics’ with mouse pathology a Comparative Pathology Program has been developed at the University of Washington . The Comparative Pathology Program is directed by Drs. Charles W. Frevert and Piper Treuting (Figure 2). Dr. Frevert is trained in internal medicine and veterinary pathology with expertise in lung pathology and has considerable experience in the use of animal models to study human disease. He is the director of the Histology and Imaging Core where he works with Dr. Judy Williams; a comparative histologist by training. Judy Williams oversees the day-to-day running of this core. The Veterinary Pathology Section is directed by Dr. Treuting, a board certified pathologist with considerable experience in mouse pathology, aging, and cancer. Dr. Denny Liggitt, a board certified pathologist, Professor and Chair of the Department of Comparative Medicine oversees this program.

Figure 2 : Organizational chart showing the many resources available to investigators through the Comparative Pathology Program.

Drs. Frevert, Treuting and Liggitt have considerable experience with mouse pathology and each have their own independent research programs. A critical role of the veterinary pathologists in this program is to assist investigators in the interpretation of data collected from live cell imaging, tissue imaging, and whole animal imaging to better understand how mouse models translate into human disease.

An important research project in CPP is a collaborative interaction with Dr. Joel Pounds at Pacific Northwest National Laboratories . This collaborative research project is investigating the use of genomics, proteonomics, and metabolonomics to identify biomarkers of lung infections. Identification of biomarkers in this project will be used to develop rapid diagnostic tests for lung infection and to integrate the data collected with lung pathology to better understand the mechanisms whereby the innate immune system recognizes and clears bacteria and viruses from the lungs.

Selected Publications

Frevert CW, Huang SL, Danaee H, Paulauskis JD, Kobzik L. Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation. J Immunol 1995;154:335-344.

Frevert CW, Matute-Bello G, Skerrett SJ, Goodman RB, Kajikawa O, Sittipunt T, Martin TR. Effect of CD14 Blockade in rabbits with Escherichia coli pneumonia and sepsis. J of Immunol 2000;164:5439-5445.

Frevert CW, Goodman RB, Kinsella MG, Kajikawa O, Ballman K, Clark-Lewis I, Proudfoot AEI, Wells TNC, Martin TR. Tissue-specific mechanisms control the retention of interleukin-8 in lungs and skin. J Immunol 2002; 168(7):3550-3556.

Frevert CW, Kinsella MG, Vathanaprida C, Goodman RB, Baskin DG, Proudfoot A, Wells T, Wight TN, Martin TR. Binding of IL-8 to Heparan Sulfate and Chondroitin Sulfate in Lung Tissue. Am J Respir Cell Mol Biol 2003;28:464-472.

Frevert CW, Sannes PL. Matrix proteoglycans as effector molecules for epithelial cell function. Eur Respir Rev 2006;14(97):1-8.

Frevert CW, Boggy G, Keenan TM, and Folch A. Measurement of cell migration in response to an evolving radial chemokine gradient triggered by a microvalve, Lab on a Chip 2006;6:849-856.

Smith LS, Kajikawa O, Elson G, Wick M, Mongovin S, Kosco-Vilbois M, Martin TR, Frevert CW. Effect of TLR4 Blockade on Pulmonary Inflammation Caused by Mechanical Ventilation and Bacterial Endotoxin, Exp Lung Res, 2008; 34(5): 225-43.

Webb-Robertson BM, Mccue LA, Beagly N, Mcdermott JE, Wunschel DS, Varnum S, Hu JZ, Isern NG, Buchko GW, Mcateer K, Skerrett SJ, Liggitt D, Pounds JG, Frevert, CW. A Bayesian Integration Model of High-Throughput Proteomics and Metabolomics Data for Improved Early Detection of Microbial Infections. Pac Symp Biocomput. In Press