Dr Karen Wright
Office C17 / Lab C2/5
Division of Biomedical and Life Sciences
Faculty of Health and Medicine
Tel: +44 1524 593548
Fax: +44 1524 593192
Current Research Interests
Role of the endogenous cannabinoid system in the human gastrointestinal tract
The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis, affect more than 100,000 people in the UK. They can give rise to symptoms of bloody diarrhoea, abdominal pain and weight loss. These diseases are characterised by recurring bouts of these symptoms over many years. Such long-term inflammation acts as a risk factor for bowel cancer. The cause of inflammatory bowel disease remains unclear and there is no cure. Drug therapy (such as steroid use) has an anti-inflammatory effect through non-specific generalised immunosuppression.
A family of molecules, termed endocannabinoids, occur naturally in the body. During the last few years, the potential medicinal use of components of the Cannabis plant in human diseases has focused much attention on the system inherent in the body that responds to both plant-derived and endogenous cannabinoids. Endocannabinoids have modulatory effects on the immune system and this may have therapeutic implications for inflammatory conditions, such as IBD.
My core research interests have concentrated on the cellular and molecular inflammatory processes involved in IBD. Using human colonic epithelial cell lines as models of inflammation, initial studies were aimed at identifying pro- and anti-inflammatory cytokine signalling pathways that impacted on nitric oxide and prostaglandin production. I then investigated the presence and function of the cannabinoid system in human intestinal tissue, in relation to intestinal inflammation. These studies examine human colonic tissue of diseased and normal origin, including colorectal cancer biopsies for comparison and involve the purification of primary colonic epithelial cells from colonic resections.
A similar approach has been undertaken to define the cannabinoid system in Crohn's Disease, specifically in the human ileum. I have been investigating how cannabinoids cooperate with other receptors and signalling pathways to modulate gastrointestinal cell migration, proliferation, differentiation and survival. Many of these pathways are dysregulated in Inflammatory Bowel Disease, particularly in relation to barrier integrity and autophagy. Identifying the regulation and function of these receptors in chronic inflammatory settings and the development of intestinal neoplasia, forms a large part of my research profile.
Importance of physiological levels of oxygen and energy sources in validating GI epithelial cell models of inflammation and cancer
Cells and tissues traditionally cultured in the laboratory do not experience the levels of oxygen or the energy sources that they would in their natural microenvironment. This does not reflect normal physiology and much of the scientific information previously gained about the cells that line the intestinal tract and the mechanisms of their responses during inflammatory processes, has not addressed this issue.
This research will 1) establish cell and tissue culture conditions that are physiologically relevant for cells in the gastrointestinal tract; and 2) redefine a cellular model of inflammation under these conditions. It is envisaged that this work will contribute new information about how these cells normally function in this physiologically relevant environment and more accurately reflect the changes that occur during intestinal inflammation, and, by so doing, improve our understanding of the mechanisms of diseases such as Crohn's Disease and Ulcerative Colitis. The project relies heavily on the generosity of patients to donate some of their intestinal tissue taken during surgical procedures and will result in better informed therapeutic targets for human gastrointestinal diseases.
Karen L. Wright, Duncan A.F. Robertson, Mary Pat Moyer and Stephen G. Ward. (2008). Long term cannabinoid receptor (CB1) blockade in obesity: implications for the development of colorectal cancer. Int J Cancer 122, 1920-1921
Karen L. Wright,, Marnie Duncan and Keith A. Sharkey. (2008) Cannabinoid (CB)-2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br. J. Pharmacol. 153(2), 263-70
Karen Coopman, Laura D. Smith, Karen L. Wright and Stephen G. Ward. (2007) Temporal variation in CB(2)R levels following T lymphocyte activation: Evidence that cannabinoids modulate CXCL12-induced chemotaxis. Int Immunopharmacol. 7(3), 360-71
Orr Ofek, Meliha Karsak, Nathalie Leclerc, Meirav Fogel, Baruch Frenkel, Karen Wright, Joseph Tam, Malka Attar-Namdar, Vardit Kram, Esther Shohami, Raphael Mechoulam, Andreas Zimmer, and Itai Bab (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. PNAS, 103(3), 696-701
Kouroumalis A, Aptel H, Nibbs RJ, Wright KL, Kolios G, Ward SG. (2005) The chemokines CXCL9, CXCL10 and CXCL11 differentially stimulate G?i-independent signalling and actin responses in human intestinal myofibroblasts. J. Immunol. 175 (8), 5403-5411
Wright KL, Rooney N, Feeney M, Tate J, Robertson DAF, Welham MJ and Ward SG. (2005) Differential expression of functional cannabinoid receptors in human colonic epithelium: evidence that cannabinoids promote wound healing. Gastroenterology 129(2), 437-453
Patel K, Wright KL, Whittaker P, Chakravarty P, Watson M and Ward SG. (2005) Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPAR? agonists: evidence for disparate functional effects which are independent of NF-?B and PPAR?. Cell Sig. 17(9), 1098-110
Wright KL, Weaver SA, Patel K, Coopman K, Feeney M, Kolios G, Robertson DAF and Ward SG. (2004) Differential regulation of prostaglandin E biosynthesis by interferon-? ?in epithelial cells. Br. J. Pharmacol. 141(7), 1091-1097
Curnock AP, Sotsios Y, Wright KL and Ward SG. (2003) Optimal Chemotactic Responses of Leukemic T Cells to Stromal Cell-Derived Factor-1 Requires the Activation of Both Class IA and IB Phosphoinositide 3-Kinases. J Immunol. 170(8), 4021-30
Freeburn RW, Wright KL, Burgess SJ, Astoul E, Cantrell DA and Ward SG. (2002) Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase effectors. J Immunol. 169(10), 5441-50
Weaver SA, Pia Russo M, Wright KL, Kolios G, Jobin C, Robertson DAF and Ward SG. (2001) Regulatory role of phosphatidylinositol 3-kinase on TNF?-induced cyclooxygenase-2 expression in colonic epithelial cells. Gastroenterology, 120(5), 1117-1127
Wright KL and Ward SG. (2000) Interactions between phosphatidylinositol 3-kinase and nitric oxide: explaining the paradox. Minireview Mol. Cell. Biol. Res. Commun., 4(3), 137-143
Kolios G, Wright KL, Linehan JD, Robertson DAF and Westick J. (2000) Interleukin-13 inhibits nitric oxide production in human colonic mucosa. Hepato-Gastroenterology 47, 714-717.
Wright KL, Kolios G, Westwick J and Ward SG. (1999) Cytokine-induced apoptosis in epithelial HT-29 cells is independent of nitric oxide formation: evidence for an IL-13-driven PI3-kinase-dependent survival mechanism. J. Biol. Chem. 276, 17193-17201
Kolios, G., Wright, K.L., Jordan, N.J., Leithead, J.B., Robertson, D.A.F. and Westwick, J. (1999) C-X-C and C-C chemokine expression and secretion by the human colonic epithelial cell line, HT-29: differential effect of T lymphocyte-derived cytokines. Eur. J. Immunol. 29, 530-536
Wright, K., Ward, S.G., Kolios, G. and Westwick, J. (1997) Activation of phosphatidylinositol 3-kinase by interleukin-13 - An inhibitory signal for inducible nitric-oxide synthase expression in the epithelial, cell line HT-29. J. Biol. Chem., 272, 12626-12633
Kolios G, Wright KL, Jordan NJ, Leithead JB, Murphy CT, Robertson DAF and Westwick J. (1997) Regulation of inflammatory mediator production in human colonic epithelial cells. Hell. J. Gastroenterol. 10, 135-147