William Parker, PhD
Division of Surgical Sciences
Department of Surgery
Duke University Medical Center
487 Med Sci Res Bldg
Box 2605 DUMC
Durham, NC 27710
Work in the Parker lab focuses on the immune system and its role in biology and disease. We are currently involved in three primary areas of investigation related to medicine, as well as basic work in protein folding. Some references are provided here, and a greatly expanded list can be found on Dr. Parker's faculty profile.
Our laboratory is interested in the support of bacterial growth in the lumen of the gut by the mammalian immune system. Current work in our laboratory suggests that the model of “immune inclusion,” outlined in the figure below, is ubiquitous in mammals and is also important in non-mammalian species (e.g., amphibians).
In this model, secretory IgA and mucin, the major component of mucus, facilitate adherence of bacteria to the proximal part of the large bowel. Thus, the immune system supports biofilm growth by commensal (beneficial) bacteria.
Use of this model of gut immunity has enabled our laboratory to achieve the first growth of bacterial biofilms on live, cultured gut epithelial cells. Further, this model provides an apparent function of the human vermiform appendix, an issue that has been in question since Leonardo da Vinci first described the appendix in 1506 A.D.
The figure above shows a model of the apparent function of the human vermiform appendix as depicted by the New York Times Magazine. In this model, the appendix, which is relatively protected from infection by pathogens due to its narrow lumen and its location away from the fecal flow, sheds mutualistic (beneficial) bacteria on a regular basis. These bacteria would be useful in re-booting the bowel following dysentery, which is one of the leading causes of death in developing countries.
Work on the immunological aspects of this project were conducted in collaboration with R. Randal Bollinger in the Department of Surgery. Work on the evolutionary aspects of this project have been conducted with evolutionary biologists, including Heather Smith in Arizona and Michel Laurin in Paris.
Everett, ML, Palestrant, D., Miller, SE, Bollinger, RR and Parker, W. Immune Exclusion and Immune Inclusion: a New Model of Host-Bacterial Interactions in the Gut. Clinical and Applied Immunology Reviews. 2004; 5: 321-332. Full text (PDF, 264 KB).
Bollinger, RR, Barbas, AS, Bush, EL, Lin, SS and Parker. W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J. Theoretical Biology. 2007; 249: 826-831. Full text (PDF, 177MB).
Smith, HF, Fisher, RE, Thomas, AD, Everett, ML, Bollinger, RR, and Parker, W. (2009) Comparative Anatomy and Phylogenetic Distribution of the Mammalian Cecal Appendix, Journal of Evolutionary Biology, 22:1984 - 1999. (Highlighted by Science magazine in the October 23rd, 2009 issue)
Laurin, M, Everett, ML, and Parker, W. The Cecal Appendix: One More Immune Component With a Funtion Disturbed By Post-Industrial Culture. The Anatomical Record 2011 DOI: 10.1002/ar.21357
Our laboratory is interested in the effects of chronic aspiration of gastric fluid on lung transplant recipients.
In pursuit of this goal, we have developed the first experimental model of chronic aspiration. Studies have demonstrated clearly, as shown in the figure below, that chronic aspiration in pulmonary allograft recipients can lead to obliterative broncheolitis, which is the hallmark of graft failure in the majority of lung transplant patients.
This provides the first re-capitulation of obliterative broncheolitis in an experimental model, providing a means by which potential treatment of this condition can be studied.
Additional studies are being conducted evaluating the effects of chronic aspiration of gastric fluid on asthma. Work on these projects is conducted in collaboration with R. Duane Davis and Shu S. Lin, both in the Department of Surgery.
Hartwig, MG, Appel, JZ III, Li, B, Hsieh, CC, Lin, SS, Parker, W and Davis, RD. Chronic Aspiration of Gastric Contents Contributes to Accelerated Pulmoary Dysfunction in a Model of Rat Lung Transplantation. J. Thorac. Cardiovasc. Surg. 2006; 131: 209-217.
Li, B, Hartwig, MG, Appel, JZ, Bush, EL, Balsara, KR, Holzknecht, ZE, Collins, BH, Howell, DN, Parker, W, Lin, SS, and Davis, RD. Chronic Aspiration of Gastric Fluid Induces Development of Obliterative Bronchiolitis in a Rat Lung Transplant Model. Am. J. Transplantation. 2008; In Press.
Barbas, AS, Downing, TE, Balsara, KR, Tan, H-E, Rubinstein, GJ, Parker, W, Davis, RD. & Lin, S.S. Chronic Aspiration shifts the Immune Response from Th-1 to Th-2 in a Murine Model of Asthma. European Journal of Clinical Investigation. 2008; In Press.
It is now widely acknowledged that the development of a wide range of immune disorders in humans is due to depletion of particular organisms from the "human biome" (the human body and the organisms associated with it) found in Westernized countries.
The Biome Depletion Theory is thought to account for both appendicitis and asthma, two diseases related to the other projects studied by our laboratory. Thus, we support that idea that to fully understand the pathogenesis of the immune-related diseases studied by our laboratory, the effects of biome depletion on the immune system must be understood.
Initial studies have focused on the striking differences between the immune systems of hygienic (laboratory) rodents and non-hygienic (wild-caught) rodents. For examples of the substantial differences, see the figure below that shows the relative inert nature of immune cells from wild rats compared to laboratory rats.
We have found that the dramatic differences between the laboratory rats (the white rats above) and the wild-caught rats (the brown-grey rat, show above) are not dependent on the strain of laboratory rat or on the colony of wild rat evaluated. These findings suggest that our observations are due to environmentally-induced factors such as biome depletion rather than genetic differences between laboratory rats and wild-caught rats.
Devalapalli A, Lesher A, Shieh K, Solow JS, Everett ML, Edala AS, Whitt P, Long R, Newton N, and Parker W. Increased Levels of IgE and Autoreactive, Polyreactive IgG in Wild Rodents: Implications for the Hygiene Hypothesis. Scand. J. Immunol. 2006; 64:125-136.
Lesher A, Li B, Whitt P, Newton N, Devalapalli AP, Shieh K, Solow JS, and Parker W. Increased IL-4 Production and Attenuated Proliferative and Proinflammatory Responses of Splenocytes from Wild-Caught Rats (Rattus Norvegicus). Immunol. and Cell Bio. 2006; 84:374-382.
In addition to the above projects related to medicine, Dr. Parker also continues some longstanding work in basic science in the field of protein folding. The main thrust of the work in this area involves testing the hypothesis that the formation of helical bundles is a primary event occurring in a general mechanism of protein folding, regardless of the native structure of the protein. Details regarding this model and the work associated with it can be found in the following references.
Parker W, and Stezowski JJ. Occurrences of Sequences with Amphiphilic a-helical Potential in b-sheet Proteins May Reveal Structural Features Important for Protein Folding. Proteins 1996; 25: 253-260.
Parker W, Sood A, and Song A. Organization of Regions with Amphiphilic a-helical potential Within the 3-dimensional Structure of b-sheet Proteins. Protein Engineering 2001; 14: 315-319. Full text (PDF, 574 KB).
Chen, E, Evetett, ML, Holzknecht, ZE, Holzknecht, RA, Lin, SS, Bowles, DE, and Parker, W (2010), Short-Lived alpha-helical Intermediates in the Folding of beta-sheet Proteins, Boichemistry 49:5609-5619.