The long-term goal is to understand intracellular mechanisms responsible for the control of active transport of chloride ions by the intestinal epithelium. This transport mechanism is the major driving force for the movement of water into the intestinal lumen. Accordingly, significant disease can result from both its under- and over-expression. Studies accomplished during the current funding period have firmly established that there are both positive and negative signalling pathways that interact to set the overall level of chloride secretion. Certain calcium- dependent agonists, such as carbachol, have dual effects on secretion, first stimulating then inhibiting subsequent chloride secretion. Peptide growth factors, such as epidermal growth factor (EGF), have been identified as epithelial agonists that inhibit chloride secretion without stimulating the process. Although carbachol and EGF inhibit chloride secretion via separate pathways, the pathways nevertheless interact because both agents activate the EGF receptor in mediating their inhibitory effects. The goal of the current studies is to define the precise mechanisms underlying the inhibitory effects of carbachol and EGF.
Three specific aims are proposed.
The first aim will focus on inhibition by carbachol, and define the upstream signals that lead to EGF receptor phosphorylation as well as the downstream targets of carbachol-stimulated mitogen-activated protein kinase activation.
The second aim will test the hypothesis that specific isoform(s) of protein kinase C mediate the inhibitory effects of EGF on chloride secretion.
The third aim will define the molecular basis of inhibitory signalling via the EGF receptor activated in response to carbachol (""""""""transactivation"""""""") versus EGF binding. The overall strategy will be to correlate biochemical and electrophysiological parameters in a well-characterized model human colonic epithelium, the T/84 cell line. The significance of he studies lies in the potential to increase our understanding of the cellular abnormalities in secretory diarrhea, cystic fibrosis and related disorders. Ultimately, improved knowledge of such abnormalities may improve therapies for these conditions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG2-RAP (02))
Program Officer
May, Michael K
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Barrett, Kim E; McCole, Declan F (2016) Hydrogen peroxide scavenger, catalase, alleviates ion transport dysfunction in murine colitis. Clin Exp Pharmacol Physiol 43:1097-1106
Hoda, M Raschid; Scharl, Michael; Keely, Stephen J et al. (2010) Apical leptin induces chloride secretion by intestinal epithelial cells and in a rat model of acute chemotherapy-induced colitis. Am J Physiol Gastrointest Liver Physiol 298:G714-21
McCole, D F; Barrett, K E (2009) Decoding epithelial signals: critical role for the epidermal growth factor receptor in controlling intestinal transport function. Acta Physiol (Oxf) 195:149-59
Scharl, Michael; Paul, Gisela; Weber, Achim et al. (2009) Protection of epithelial barrier function by the Crohn's disease associated gene protein tyrosine phosphatase n2. Gastroenterology 137:2030-2040.e5
Chappell, Alfred E; Bunz, Michael; Smoll, Eric et al. (2008) Hydrogen peroxide inhibits Ca2+-dependent chloride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins. FASEB J 22:2023-36
Tillinger, Wolfgang; McCole, Declan F; Keely, Stephen J et al. (2008) Hypertonic saline reduces neutrophil-epithelial interactions in vitro and gut tissue damage in a mouse model of colitis. Am J Physiol Regul Integr Comp Physiol 295:R1839-45
McCole, Declan F; Barrett, Kim E (2007) Varied role of the gut epithelium in mucosal homeostasis. Curr Opin Gastroenterol 23:647-54
McCole, Declan F; Truong, Anh; Bunz, Michael et al. (2007) Consequences of direct versus indirect activation of epidermal growth factor receptor in intestinal epithelial cells are dictated by protein-tyrosine phosphatase 1B. J Biol Chem 282:13303-15
Keely, Stephen J; Scharl, Michael M; Bertelsen, Lone S et al. (2007) Bile acid-induced secretion in polarized monolayers of T84 colonic epithelial cells: Structure-activity relationships. Am J Physiol Gastrointest Liver Physiol 292:G290-7
Chow, Jimmy Y C; Barrett, Kim E (2007) Role of protein phosphatase 2A in calcium-dependent chloride secretion by human colonic epithelial cells. Am J Physiol Cell Physiol 292:C452-9

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