Professor Egan graduated from UCG in 1990 (M.B., B.Ch., B.A.O.), and completed internship, house officer and registrar training, based at University College Hospital Galway.  He received Membership of RCPI in 1992, and Masters in Medical Science from UCG in 1994.  From 1994 to 1999, at the Mayo Clinic in Minnesota he completed further training in Internal Medicine, Clinical pharmacology & Gastroenterology, receiving American Board certification in those 3 disciplines.  NUI Galway conferred an MD in 1999.  Prof. Egan then undertook post-doctoral training from 2000 to 2002, in the Laboratory of Mucosal Immunology at the University of California, San Diego, before returning to the Mayo Clinic to take up a consultancy in Gastroenterology, with joint appointment in the Department of Molecular Pharmacology and Experimental Therapeutics.  His research focuses on molecular characterization of signaling pathways involved in intestinal epithelial cell stress, death and malignant transformation.  In 2005, Prof. Egan was recruited by NUI Galway and the Health Service Executive West as Professor of Clinical Pharmacology/Consultant Clinical Pharmacologist and Head of the Department of Pharmacology & Therapeutics, a position he took up in August 2005.

Research

Programme Title  gIntestinal epithelial injury, repair and carcinogenesish

Project 1.         Molecular regulation of NF"{B activation in inflammatory colon cancer. 

NF"{B constitutes a ubiquitously expressed family of inducible dimeric transcription factors that regulate the expression in many genes whose encoded products affect immune functions and cell death decisions.  NF"{B proteins reside primarily in the cytoplasm of almost all mammalian cells, retained at that location by a family of inhibitors termed I"{Bs.  Many cellular stresses activate signal pathways that lead to phosphorylation and subsequent degradation of I"{Bs by the multi-subunit IKK complex.  One of the components of this subunit,  IKKfÀ, is critical for I"{Ba phosphorylation and degradation which leads to NF"{B activation.  We have studied the role of this kinase in intestinal epithelial pathophysiology by generating a mouse strain that lacks this kinase in intestinal epithelial cells.  Results of experiments conducted using these mice have revealed that NF"{B is important for the promotion of inflammation in the intestinal tract and for the blocking of apoptosis, which seems to correlate with the development of epithelial cancer.  NF"{B also seems to be important for the blockade of apoptosis induced by ionising radiation.   

Our current investigations are directed at understanding the molecules and pathways involved in the persistent activation of NF"{B in the setting of chronic inflammation of the colon.  The significance of this work relates to the fact that many gastrointestinal carcinomas, including colorectal cancer, occur more commonly in patients with chronic inflammation of that organ such as ulcerative colitis.  Other studies are directed at understanding the importance of NF"{B in protecting stem cells of the colonic epithelium from radiation-induced death.  The importance of these studies relates to the fact that colonic epithelial stem cells are important for controlling homeostasis of the entire colon and also for initiating cancer development.

Project 2. Evasion of immune surveillance by colon cancer metastases: molecular mechanisms.  

Metastatic spread of colorectal cancer prevents the cure of this disease, so novel therapies that could prevent of successfully treat metastases are needed.  The liver is a frequent site of colorectal cancer metastatic deposits.  Natural killer cells and NK T cells in the liver serve to protect against metastases through the expression of the death ligand TRAIL, which induces apoptosis of invading TRAIL receptor-expressing cancer cells.  How colon cancer cells evade TRAIL mediated apoptosis in the liver is not understood.

Our initial results have defined a role for a previously unrecognised NFkB target gene, OPG in the blockade of TRAIL-induced apoptosis of colon cancer cells. Current work is directed at analysing the importance of NFkB, through upregulated expression of OPG in the neutralisation of TRAIL mediated apoptosis of colon cancer cells as they invade the liver during metastatic dissemination. 

Recent Publications:

  • Egan LJ, Sandborn WJ, Mays DC, Tremaine WJ, Lipsky JJ. The intestinal and systemic pharmacokinetics of methotrexate in inflammatory bowel disease patients. Clinical Pharmacology & Therapeutics, 1999;65:29-39.
  • Egan LJ, Sandborn WJ, Mays DC, Tremaine WJ, Lipsky JJ. Plasma and rectal adenosine in inflammatory bowel disease: effect of methotrexate. Inflammatory Bowel Diseases, 1999;5:167-173.
  • Egan LJ, Mays DC, Huntoon CJ, Bell MP, Pike MG, Sandborn WJ, Lipsky JJ, McKean DJ. Inhibition of interleukin-1-stimulated NF-kB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity. Journal of Biological Chemistry 1999;274:26448-26453.
  • Egan LJ, Sandborn WJ, Tremaine WJ, Leighton JA, Mays DC, Pike MG, Zinsmeister AR, Lipsky JJ. A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohnfs disease and ulcerative colitis.Alimentary Pharmacology & Therapeutics,  1999; 13:1597-1604.
  • Egan LJ, Murray JA. New perspectives in gastric acid suppression: genetic polymorphisms predict the efficacy of proton pump inhibitors. Digestive Diseases, 2000;18:58-63.
  • Egan LJ, Baron TH. Endoscopic removal of an embedded biliary Wallstent by piecemeal extraction. Endoscopy, 2000;32:492-4.
  • Egan LJ, Sandborn WJ, Tremaine WJ, Mays DC, Lipsky JJ. Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate in treatment resistant inflammatory bowel disease. Inflammatory Bowel Diseases 2000;6:286-9.
  • Berin MC, Darfeuille-Michaud A, Egan LJ, Miyamoto Y, Kagnoff MF. Role of EHEC O157:H7 virulence factors in the activation of intestinal epithelial cell NF-kB and MAP kinase pathways and the upregulated expression of interleukin-8 .  Cellular Microbiology 2002;4:635-647.
  • Chen L-W, Egan LJ Li Z-W,. Kagnoff MF, Karin M. The two faces of IKK and NF-kB inhibition, prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion.  Nature Medicine, 2003;9(5):575-581.
  • Egan LJ, Myhre GM, Mays DC, Dierkhising RA, Kammer PP, Murray JA. CYP2C19 pharmacogenetics in the clinical use of proton-pump inhibitors for gastro-esophageal reflux disease: variant alleles predict gastric acid suppression, but not esophageal acid exposure or reflux symptoms. Alimentary Pharmacology & Therapeutics 2003;17(12):1521-1528.
  • Egan LJ, De Lecea A, Lehrman ED, Myhre GM, Eckmann L, Kagnoff MF. Nuclear factor kB activation promotes restitution of wounded intestinal epithelial monolayers. American Journal of Physiology: Cell Physiology 2003;285(5):C1028-C1035 .
  • Colombel J-F, Loftus EV Jr, Tremaine WJ, Egan LJ, Harmsen WS, Schleck CD, Zinsmeister AR, Sandborn WJ.  The safety profile of Infliximab in patients with Crohn's disease: The Mayo Clinic experience in 500 patients.  Gastroenterology2004;126(1):19-31.
  • Egan LJ, Eckmann L, Greten F, Chae S, Li Z-W, Myhre GM, Robine S, Karin M, Kagnoff MF.  IKKb-dependent NF-kB activation provides radioprotection to the intestinal epithelium.  Proceedings of the National Academy of Sciences USA, 2004;101:2452-2457.
  • Egan LJ, Sandborn WM.  Advances in the treatment of Crohn's disease .  Gastroenterology 2004; 126(6):1574-81.
  • Maaser C, Egan LJ, Birkenbach MP, Eckmann L, Kagnoff MF.  Expression of EBI3 and related molecules by human intestinal epithelium.  Immunology, 2004: 112(3):437-45.
  • Loftus CG, Egan LJ, Sandborn WJ.  Cyclosporine, Tacrolimus and Mycophenolate Mofetil in the treatment of inflammatory bowel disease.  Gastroenterology Clinics of North America 2004;33(2):141-69.
  • Greten FR, Eckmann L, Greten TF, Park J-M, Li Z-W, Egan LJ, Kagnoff MF, Karin M.  IKKb links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell, 2004;118:285-296 .
  • Myhre GM, Toruner M, Abraham S, Egan LJ.  Metalloprotease disintegrin-mediated ectodomain shedding of EGFR ligands promotes intestinal epithelial restitution.  American Journal of Physiology: Gastrointestinal and Liver Physiology,10.1152/ajpgi.00253.2004 .
  • Thomas C, Myhre GM, Tschumper R, Sreekumar R, Jelinek D, McKean DJ, Sandborn WJ, Lipsky JJ,  Egan LJ. Selective inhibition of inflammatory gene expression in activated T lymphocytes: a mechanism of immune suppression by thiopurines.Journal of Pharmacology and Experimental Therapeutics, 2005; 312(2):537-45.
  • Egan LJ.  Drug interactions in gastroenterology: mechanisms, consequences and how to avoid.  Clinical Gastroenterology and Hepatology, 2004;2(9):725-30.
  • Toruner M, Harewood GC, Loftus EV Jr, Sandborn WJ, Tremaine WJ, Faubion WA, Schroeder KW, Egan LJ. Endoscopic factors in the diagnosis of colorectal dysplasia in chronic inflammatory bowel disease. Inflammatory Bowel Diseases,2005;11(5):428-34.
  • Moolsintong P, Loftus EV Jr, Chari ST, Egan LJ, Tremaine WJ, Sandborn WJ.  Acute pancreatitis in Crohn's disease: clinical features and outcomes. Inflammatory Bowel Diseases. 2005 Dec;11(12):1080-4.
  • Egan LJ, Derijks LJ, Hommes D. Pharmacogenomics in inflammatory bowel disease. Clinical Gastroenterology and Hepatology, 2006 Jan;4(1):21-8.
  • Toruner M, Fernandez-Zapico M,Sha JJ, Pham L, Urrutia R, Egan LJ. Anti-anoikis effect of nuclear factor-kappa B through upregulated expresion of osteoprotegerin, BCL-2 and IAP-1. Journal of Biological Chemistry. 2006 Jan 5; to follow
  • Chopra A, Pardi DS, Loftus EV Jr, Tremaine WJ, Egan LJ, Faubion WA, Hanson KA, Johnson TA, Sandborn WJ.  Budesonide in the treatment of inflammatory bowel disease: the first year of experience in clinical practice. Inflammatory Bowel Disease.  2006 Jan;12(1):29-32.
  • Egan LJ, Sandborn WJ. Positioning novel biologic, probiotic, and apheresis therapies for Chronfs disease and ulcerative colitis. Current Gastroenterology Reports. 2005 Dec;7(6):485-91

Contact details

E-mail:   laurence.egannuigalway.ie 
Telephone: 353 91 495355, ext. 5355 
Fax:               00 353 91 495572

Location:     Clinical Science Institute