Gastrointestinal Physiology Lab
The long-term objective of this research laboratory is to study mechanisms responsible for maintenance and restoration of the intestinal barrier, with the ultimate objective of pharmacologically restoring the mucosal barrier in patients suffering from diseases associated with increased intestinal permeability. Restoring the intestinal barrier would be of particular significance in patients suffering from diseases such as intestinal ischemia/reperfusion injury because of the rapid onset of sepsis and multiple organ failure associated with translocation of bacteria and associated toxins across damaged intestinal epithelium.
The laboratory collaborates extensively with the Leukocyte Biology Laboratory and the Center for Gastrointestinal Biology and Disease at UNC-Chapel Hill.
Lab Members
Anthony Blikslager, Principal Investigator Vanessa Cook, Doctoral Candidate
John Marshall, Doctoral Candidate
Adam Moeser, Post Doctoral GI Research Fellow
Meghali Nighot, Research Technician
Prashant Nighot, Doctoral Candidate
Kathleen Ryan, Research Specialist
Jenna Wooten, Doctoral Candidate
Research
We have two current research focuses, funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and the National Research Initiative of the United States Department of Agriculture respectively.
Mechanisms of Prostaglandin-induced Intestinal Repair
NIH Grant # DK53284
The central hypothesis for these studies (figure) is that PGI2 and PGE2 are elaborated by inducible cyclooxygenase-2 (COX-2) during intestinal injury from sub-epithelial fibroblasts and restore barrier function by signaling closure of inter-epithelial tight junctions. Tight junctions close in response to a synergistic signal between intracellular calcium and cyclic AMP, which are increased by PGI2-stimulated cholinergic nerves and PGE2 receptor-linked adenylate cyclase respectively.
Mechanisms of Intestinal Repair in the Horse
USDA NRI Grant # 98-02537
The central hypothesis for these studies is that neutrophil-elaborated oxidants prevent prostaglandin-induced collapse of the paracellular space by loosening intercellular tight junctions. We further postulate that inhibition of tyrosine phosphorylation of the key tight junction regulatory protein zonula occludens-1 (ZO-1) by genistein will trigger closure of loosened tight junctions, restoring the ability of prostaglandins to rescue barrier function and reduce the absorption of bacterial lipopolysaccharide (LPS).
Recent Publications
Basic Science
Blikslager AT, Pell SM, Young KM. PGE-2 triggers recovery of transmucosal resistance via EP receptor crosstalk in porcine ischemia-injured ileum. Am J Physiol Gastrointest Liver Physiol 2001; 281:G375-81.
Blikslager AT, Hunt E, Guerrant R, Rhoads M, Argenzio RA. Glutamine transporter in crypts compensates for loss of villus absorption in bovine cryptosporidiosis. Am J Physiol Gastrointest Liver Physiol, in press.
Blikslager AT, Roberts MC, Young, KM, Rhoads JM, Argenzio RA. Genistein augments prostaglandin-induced recovery of barrier function in ischemic-injured porcine ileum. Am J Physiol, 2000;278:G207-G216.
Rhoads JM, Argenzio RA, Chen W, Graves LM, Licato LL, Blikslager AT, Smith J, Gatzy, Brenner DA. Glutamine metabolism stimulates intestinal cell MAPKs by a cAMP-inhibitable, Raf-independent mechanism. Gastoenterology, 2000;118:90-100.
Blikslager AT, Roberts MC, Argenzio RA. Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum. J Clin Invest 1997;100:1928-1933.
Blikslager AT, Roberts MC. Nitric oxide and the intestinal epithelial barrier: does it protect or damage the gut? J Ped Gastroenterol Nutr 1997;25:439-440.
Blikslager AT, Roberts MC, Rhoads JM, Argenzio RA. How important is reperfusion injury following porcine intestinal ischemia? Surgery 1997;121:526-534.
Ahdieh N, Blikslager AT, Bhat BG, Coleman RA, Argenzio RA, Rhoads JM. L-Glutamine and transforming growth factor alpha enhance recovery of monoacylglycerol acyltransferase and diacylglycerol acyltransferase activity in porcine post-ischemic ileum. Pediatr Res 1998;43:227-233.
Blikslager AT, Roberts MC, Argenzio RA. Prostaglandin-induced recovery of epithelial barrier function in porcine ileum is triggered by chloride secretion. Am J Physiol, 1999;276:G28-G36.
Blikslager AT, Rhoads JM, Bristol DG, Roberts MC, Argenzio RA. Glutamine and TGF-a synergistically enhance repair of intestinal ischemia/ reperfusion injury. Surgery 1999;125:186-194.
Equine Studies
Gayle JM, Blikslager AT, Bowman KF. Mesenteric rents as a source of small intestinal strangulation in horses: 15 horses (1990-1997). JAVMA 2000; 216:1446-1449.
Campbell NB, Blikslager AT. The role of cyclooxygenase inhibitors in repair of ischemic-injured jejunal mucosa in the horse. Equine Vet J Suppl 2000;32:59-64.
Gayle JM, Blikslager AT, Jones SL. Role of neutrophils in intestinal mucosal injury. J Am Vet Med Assoc 2000;217:498-500.
Blikslager AT, Roberts MC, Argenzio RA. How important is intestinal reperfusion injury in the horse? J Am Vet Med Assoc 1997;211:1387-1389.
Blikslager AT, Roberts MC. Mechanisms of intestinal repair. J Am Vet Med Assoc 1997;211:1437-1441
Blikslager AT. Do we need cyclooxygenase-2 inhibitors in equine practice? Comp Contin Educ Pract Vet 1999;21:548-550.
Gerard MP, Blikslager AT, Roberts MC, Tate LP, Argenzio RA. The characteristics of intestinal injury peripheral to strangulating obstruction lesions in the equine small intestine. Equine Vet J, 1999, in press.
Campbell NB, Blikslager AT. The role of cyclooxygenase inhibitors in repair of ischemic-injured jejunal mucosa in the horse. Equine Vet J 1999, in press.
Education
The lab offers graduate training through the Physiology Program, an interdepartmental group drawn from the animal science, biochemistry, entomology, clinical sciences, poultry science, psychology, veterinary anatomy, physiological sciences & radiology, and zoology departments. The program emphasizes the comparative approach implicit in this type of organization and is designed to prepare individuals for careers in research and teaching.
Please contact the PI regarding training and funding opportunities.
GI journal club (PHY 620) schedule
Room D-330, Fridays, 7:45am
Links
Journals
Journal of Clinical Investigation
Gastroenterology
American Journal of Physiology
Journal of Pharmacology and Experimental Therapeutics
Chemical and Biotechnology Companies
Sigma
Cayman Chemical
Fisher
ICN
Biomol
Boehringer Ingelheim
VMRD (veterinary antibodies)
Professional Organizations
American Gastroenterological Association
American Veterinary Medical Association
American Association of Equine Practitioners
American College of Veterinary Internal Medicine
American College of Veterinary Surgeons