Michael B. Dwinell, PhD
Associate Professor
Microbiology and Molecular Genetics
Medical College of Wisconsin
Director, Bobbie Nick Voss Laboratory for Colon Cancer Research
Research Focus: Mucosal Immunity; Immune Regulation in Cancer
PhD: University of Wisconsin, Madison (1996) Gastrointestinal Pathophysiology
Postdoctoral Training: University of California, San Diego; Mucosal Immunology
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The Bobbie Nick Voss laboratory utilizes molecular, biochemical, cellular and genetic approaches in combination with human in vitro cell culture and murine in vivo model systems. Those experimental approaches are used to define the mechanisms whereby innate defense responses within the mucosal epithelium are regulated in human health and disease. Completion of these studies will strengthen our ability to identify means by which those responses can be specifically manipulated and therapeutically targeted. These studies are relevant to understanding the inflammatory bowel diseases, colorectal cancer, and infections with disease causing food- and water-borne pathogens.
The cells of the intestinal epithelium constitute an essential component of the mucosal immune system forming a dynamic physical barrier to prevent or limit entry of potentially noxious stimuli (Model). This epithelial barrier is injured or damaged by pathogens or upon excessive stimulation with inflammatory mediators including cytokines, chemokines, and reactive oxygen metabolites (red arrow). Immune effector molecules, including chemokines and defensins within the surrounding tissue are critical for effective host defense. Work in the laboratory indicates several of those host defense mediators bind and activate receptors on epithelial cells to regulate homeostatic growth and differentiation or initiate repair processes needed for a healthy mucosal barrier (green arrow). In cancers of the colon, breast, and lung epithelial maintenance and repair processes become dysregulated during neoplastic transformation leading to disorganization of the epithelial innate barrier (yellow arrow). Cells in the carcinoma can become invasive and motile leading to their migration, metastasis, to distant tissue sites.
Research projects in my lab include:
- Innate Immune Barrier Repair. These studies are investigating the impact of chemokines on maintenance and repair of the mucosal epithelium. Human model intestinal epithelia and transgenic murine models are being used to expand the paradigm that chemokines solely regulate leukocyte cell trafficking. Research from the laboratory show for the first time that a battery of chemokines can regulate mucosal wound healing, epithelial cell adhesion and migration processes necessary for innate immune defense.
- Chemokines in Cancer. These studies are defining the role for chemokines in tumor metastasis and carcinogenesis. Cancer of the human colon, breast, and lung represent a failure in normal epithelial growth, differentiation, and migration. Human carcinoma cell lines as well as murine models of tumorigenesis and metastasis are being used to define the molecular events regulating transcription of chemokine genes and the functional impact of those molecules in tumor growth, adhesion, invasion and metastasis.
- Innate Defense against Pathogens. These investigations are delineating innate immune responses of epithelial cells infected by microbial pathogens. Enteric pathogens utilize a number of different host colonization strategies, with interactions at the intestinal epithelium being the common pathogenic feature. Studies completed within the laboratory are defining the cellular and biochemical mechanisms epithelial cells utilize to limit disease following infection by food- or water-borne microbes.
Research in the Dwinell laboratory continues to be supported through grants from the National Institutes of Health and the Crohn’s and Colitis Foundation of America. Additional support comes from the Medical College of Wisconsin Digestive Disease Center, the Cancer Center (http://www.mcw.edu/cancercenter) and kind charitable gifts from the Bobbie Nick Voss Charitable Funds (http://www.bobbiesays.com).
Recent Publications
Wendt MK, Drury LJ, Vongsa RA, Dwinell MB. Constitutive CXCL12 expression induces anoikis in colorectal carcinoma cells. Gastroenterology. 2008 Aug;135(2):508-17. Epub 2008 May 15.
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Zimmerman NP, Vongsa RA, Wendt MK, Dwinell MB. Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease. Inflamm Bowel Dis. 2008 Jul;14(7):1000-11.
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Wendt MK, Cooper AN, Dwinell MB. Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene. 2008 Feb 28;27(10):1461-71. Epub 2007 Sep 3.
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Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB. Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene. 2006 Aug 17;25(36):4986-97. Epub 2006 Mar 27.
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Johanesen PA, Dwinell MB. Flagellin-independent regulation of chemokine host defense in Campylobacter jejuni-infected intestinal epithelium. Infect Immun. 2006 Jun;74(6):3437-47.
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Binion DG, Kugathasan S, Dwinell MB. Molecular stratification of Crohn's disease by chemokine receptors: fractalkine receptor polymorphisms define a fibrostenosing ileal subgroup. Am J Gastroenterol. 2006 Jan;101(1):107-9.
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Yang CC, Ogawa H, Dwinell MB, McCole DF, Eckmann L, Kagnoff MF. The Chemokine Receptor CCR6 Transduces Signals that Activate p130Cas and Alter cAMP-Stimulated Ion Transport in Human Intestinal Epithelial Cells. Am J Physiol Cell Physiol. 2005 Feb;288(2):C321-8. Epub 2004 Oct 13.
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Smith JM, Johanesen PA, Wendt MK, Binion DG, Dwinell MB. CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity. Am J Physiol Gastrointest Liver Physiol. 2005 Feb;288(2):G316-26. Epub 2004 Sep 9.
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Heidemann J, Ogawa H, Rafiee P, Lugering N, Maaser C, Domschke W, Binion DG, Dwinell MB. Mucosal angiogenesis regulation by CXCR4 and its ligand CXCL12 expressed by human intestinal microvascular endothelial cells. Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G1059-68. Epub 2004 Feb 05.
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Dwinell MB, Ogawa H, Barrett KE, Kagnoff MF. SDF-1/CXCL12 regulates cAMP production and ion transport in intestinal epithelial cells via CXCR4. Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G844-50. Epub 2003 Dec 18.
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Rafiee P, Ogawa H, Heidemann J, Li MS, Aslam M, Lamirand TH, Fisher PJ, Graewin SJ, Dwinell MB, Johnson CP, Shaker R, Binion DG. Isolation and characterization of human esophageal microvascular endothelial cells: mechanisms of inflammatory activation. Am J Physiol Gastrointest Liver Physiol. 2003 Dec;285(6):G1277-92. Epub 2003 Aug 14.
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Dwinell MB, Johanesen PA, Smith JM. Immunobiology of epithelial chemokines in the intestinal mucosa. Surgery. 2003 Jun;133(6):601-7. Review.
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Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel HR, Otterson MF, Ota DM, Lugering N, Domschke W, Binion DG. Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem. 2003 Mar 7;278(10):8508-15. Epub 2002 Dec 20.
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Berin MC, Dwinell MB, Eckmann L, Kagnoff MF. Production of MDC/CCL22 by human intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2001 Jun;280(6):G1217-26.
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Izadpanah A, Dwinell MB, Eckmann L, Varki NM, Kagnoff MF. Regulated MIP-3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am J Physiol Gastrointest Liver Physiol. 2001 Apr;280(4):G710-9.
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Dwinell MB, Lugering N, Eckmann L, Kagnoff MF. Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. Gastroenterology. 2001 Jan;120(1):49-59.
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Eckmann L, Smith JR, Housley MP, Dwinell MB, Kagnoff MF. Analysis by high density cDNA arrays of altered gene expression in human intestinal epithelial cells in response to infection with the invasive enteric bacteria Salmonella. J Biol Chem. 2000 May 12;275(19):14084-94.
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Merendino N, Dwinell MB, Varki N, Eckmann L, Kagnoff MF. Human intestinal epithelial cells express receptors for platelet-activating factor. Am J Physiol. 1999 Oct;277(4 Pt 1):G810-8.
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Dwinell MB, Eckmann L, Leopard JD, Varki NM, Kagnoff MF. Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology. 1999 Aug;117(2):359-67.
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Contact Information
Email: mdwinell@mcw.edu
Phone: 414-955-7427
Room: BSB-208