Dr Karen WrightLecturer
Dr Wright's research spans the cellular and molecular mechanisms of the cannabinoid system in gastrointestinal epithelium to the translational aspects of realising the therapeutic potential of cannabinoids in diseases such as Crohn's Disease, Ulcerative Colitis and colorectal cancer. Existing projects include intestinal barrier and permeability studies.
She is currently developing a new model of intestinal tissue culture that takes into account physiological levels of oxygen and energy sources, in partnership with GI physicians, surgeons and pathologists at the Royal Lancaster Infirmary and involves patients and human volunteers.
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.
PhD Supervision Interests
Cannabinoid receptor signalling bias in ex vivo intestinal organoids. Importance of physiological levels of oxygen and energy sources in validating GI epithelial cell models of inflammation and cancer. Contribution of enteroendocrine cells to cannabinoid modulation of intestinal barrier permeability function (with John Worthington). Ethical considerations of human organoid donation and research (with Laura Machin and John Appleby). Impact of cannabinoids on free living ciliates (with Jackie Parry). Students can also apply for MSc by research for the last three projects.
The role of CB1 in intestinal permeability and inflammation
Karwad, M.A., Couch, D.G., Theophilidou, E., Sarmad, S., Barrett, D.A., Larvin, M., Wright, K.L., Lund, J.N., O'Sullivan, S.E. 08/2017 In: FASEB Journal. 31, 8, p. 3267-3277. 11 p.
Cannabidiol Reduces Leukemic Cell Size - But Is It Important?
Kalenderoglou, N., Macpherson, T., Wright, K.L. 24/03/2017 In: Frontiers in Pharmacology. 8, 9 p.
Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα
Karwad, M.A., Macpherson, T., Wang, B., Theophilidou, E., Sarmad, S., Barrett, D.A., Larvin, M., Wright, K.L., Lund, J.N., O'Sullivan, S.E. 02/2017 In: FASEB Journal. 31, 2, p. 469-481. 13 p.
Raman spectroscopy: an evolving technique for live cell studies
Smith, R., Wright, K.L., Ashton, L. 21/06/2016
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Wright, K.L. 21/01/2016 In: Autophagy. 12, 1, 222 p.
Cannabinoid-induced autophagy regulates suppressor of cytokine signaling (SOCS)-3 in intestinal epithelium
Koay, L., Rigby, R., Wright, K. 15/07/2014 In: American Journal of Physiology-Gastrointestinal and Liver Physiology. 307, p. G140-G148. 9 p.
Physiological intestinal oxygen modulates the Caco-2 cell model and increases sensitivity to the phytocannabinoid cannabidiol
MacPherson, T., Armstrong, J., Criddle, D., Wright, K. 2014 In: In Vitro Cellular and Developmental Biology - Animal. 50, 5, p. 417-426. 10 p.
Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability
Alhamoruni, A., Wright, K., Larvin, M., O'Sullivan, S.E. 04/2012 In: British Journal of Pharmacology. 165, 8, p. 2598-610. 13 p.
Safety of medicine and the use of animals in research
Archibald, K., Baxter, A.D., BéruBé, K., Bunton, D., Clotworthy, M., Coleman, B., Foster, C.S., Hillier, C., McFarlane, M., Patel, A., Pierscionek, B., Root, J., Thomas, G., Tsaioun, K., Wilkinson, J.M., Wilmut, I., Wright, K.L. 29/10/2011 In: The Lancet. 378, 9802, 1 p.
Open letter to UK Prime Minister David Cameron and Health Secretary Andrew Lansley on safety of medicines
Archibald, K., Coleman, R., Foster, C., Wright, K. 4/06/2011 In: The Lancet. 377, 9781, p. 1915. 1 p.
Pharmacological effects of cannabinoids on the Caco-2 cell culture model of intestinal permeability.
Alhamoruni, A., Lee, A.C., Wright, K.L., Larvin, M., O'Sullivan, S.E. 10/2010 In: Journal of Pharmacology and Experimental Therapeutics. 335, 1, p. 92-102. 11 p.
Long term cannabinoid receptor (CB1) blockade in obesity : implications for the development of colorectal cancer.
Wright, K.L., Robertson, D.A.F., Moyer, M.P., Ward, S.G. 15/04/2008 In: International Journal of Cancer. 122, 8, p. 1920-1921. 2 p.
Cannabinoid CB2 receptors in the gastrointestinal tract : a regulatory system in states of inflammation.
Wright, K.L., Duncan, M., Sharkey, K.A. 01/2008 In: British Journal of Pharmacology. 153, 2, p. 263-270. 8 p.
Temporal variation in CB2R levels following T lymphocyte activation : evidence that cannabinoids modulate CXCL12-induced chemotaxis.
Coopman, K., Smith, L.D., Wright, K.L., Ward, S.G. 03/2007 In: International Immunopharmacology. 7, 3, p. 360-371. 12 p.
Peripheral cannabinoid receptor, CB2, regulates bone mass.
Ofek, O., Karsak, M., Leclerc, N., Fogel, M., Frenkel, B., Wright, K., Tam, J., Attar-Namdar, M., Kram, V., Shohami, E., Mechoulam, R., Zimmer, A., Bab, I. 17/01/2006 In: Proceedings of the National Academy of Sciences. 103, 3, p. 696-701. 6 p.
The Chemokines CXCL9, CXCL10, and CXCL11 Differentially Stimulate Gαi-Independent Signaling and Actin Responses in Human Intestinal Myofibroblasts.
Kouroumalis, A., Nibbs, R.J., Aptel, H., Wright, K.L., Kolios, G., Ward, S.G. 15/10/2005 In: Journal of Immunology. 175, 8, p. 5403-5411. 9 p.
Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPARγ agonists: evidence for disparate functional effects which are independent of NF-κB and PPARγ
Patel, K.M., Wright, K.L., Whittaker, P., Chakravarty, P., Watson, M.L., Ward, S.G. 09/2005 In: Cellular Signalling. 17, 9, p. 1098-1110. 13 p.
Differential Expression of Cannabinoid Receptors in the Human Colon : Cannabinoids Promote Epithelial Wound Healing.
Wright, K., Rooney, N., Feeney, M., Tate, J., Robertson, D., Welham, M., Ward, S. 08/2005 In: Gastroenterology. 129, 2, p. 437-453. 17 p.
Differential regulation of prostaglandin E biosynthesis by interferon-γ in colonic epithelial cells.
Wright, K.L., Weaver, S.A., Patel, K., Coopman, K., Feeney, M., Kolios, G., Robertson, D.A.F., Ward, S.G. 04/2004 In: British Journal of Pharmacology. 141, 7, p. 1091-1097. 7 p.
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.
Curnock, A.P., Sotsios, Y., Wright, K.L., Ward, S.G. 15/04/2003 In: Journal of Immunology. 170, 8, p. 4021-4030. 10 p.
Evidence That SHIP-1 Contributes to Phosphatidylinositol 3,4,5-Trisphosphate Metabolism in T Lymphocytes and Can Regulate Novel Phosphoinositide 3-Kinase Effectors.
Freeburn, R.W., Wright, K.L., Burgess, S.J., Astoul, E., Cantrell, D.A., Ward, S.G. 15/11/2002 In: Journal of Immunology. 169, 10, p. 5441-5450. 10 p.
Regulatory role of phosphatidylinositol 3-kinase on TNF-α-induced cyclooxygenase 2 expression in colonic epithelial cells.
Weaver, S.A., Russo, M.P., Wright, K.L., Kolios, G., Jobin, C., Robertson, D.A.F., Ward, S.G. 04/2001 In: Gastroenterology. 120, 5, p. 1117-1127. 11 p.
Interactions between Phosphatidylinositol 3-Kinase and Nitric Oxide: Explaining the Paradox
Wright, K.L., Ward, S.G. 09/2000 In: Molecular Cell Biology Research Communications. 4, 3, p. 137-143. 7 p.
Interleukin-13 inhibits nitric oxide production in human colonic mucosa.
Kolios, G., Wright, K.L., Linehan, J.D., Robertson, D.A.F., Westick, J. 2000 In: Hepato-Gastroenterology. 47, p. 714-717. 4 p.
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.
Wright, K., Kolios, G., Westwick, J., Ward, S.G. 11/06/1999 In: Journal of Biological Chemistry. 274, 24, p. 17193-17201. 9 p.
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.
Kolios, G., Wright, K.L., Jordan, N.J., Leithead, J.B., Robertson, D.A.F., Westwick, J. 02/1999 In: European Journal of Immunology. 29, 2, p. 530-536. 7 p.
Activation of phosphatidylinositol 3-kinase by interleukin-13 - An inhibitory signal for inducible nitric-oxide synthase expression in the epithelial, cell line HT-29.
Wright, K., Ward, S.G., Kolios, G., Westwick, J. 9/05/1997 In: Journal of Biological Chemistry. 272, p. 12626-12633. 8 p.
Regulation of inflammatory mediator production in human colonic epithelial cells.
Kolios, G., Wright, K.L., Jordan, N.J., Leithead, J.B., Murphy, C.T., Robertson, D.A.F., Westwick, J. 1997 In: Hellenic Journal of Gastroenterology. 10, 2, p. 135-147. 13 p.