Short bowel syndrome is a devastating clinical condition which leads to dehydration, muscle wasting, debilitation and death. Although the residual bowel has the capacity to adapt to its reduced surface area, this process is often inadequate and may require lifetime total parenteral nutrition, a modality with serious metabolic and economic consequences. Growth factors can improve adaptation in part by increasing the enterocyte's ability to transport luminal nutrients. A major nutrient glutamine (GLN) is the primary oxidative fuel for the enterocyte. The parenteral administration of epidermal growth factor (EGF) and/or human growth hormone (GH) increases sodium-dependent glutamine transport after 70% enterectomy in rabbits. The specific timing, route of administration, mechanisms of action, and potential synergistic effects of these two compounds remain to be elucidated. EGF binding activates the EGF receptor (EGFR). In cell suspensions derived from both human jejunum and C2BBE1cell line, EGF increases glutamine transport, upregulation is blocked by tyrosine kinase inhibitors which implicates a role for EGFR signaling transduction pathways. GH independently may also act through EGFR. It is hypothesized that the combination of EGF and GH upregulate sodium-dependent glutamine transport through EGFR signal transduction pathways.
The specific aims of the proposal are to 1) optimize glutamine transport mediated by EGF/GH through EGFR in rabbits after massive enterectomy; 2) determine the involvement of EGFR signal transduction pathways in altering glutamine transport by EGF/GH exposure in C2BBE1cell line; 3) to investigate the effects of EGF/GH via EGFR in upregulating glutamine transport in human small bowel. The investigators plan to use three models of small bowel function: 70% enterectomy in the rabbit, the human cell line C2BBE1 in Transwells and human small bowel as an enterocyte suspension or as a neurovascularly intact loop. It is hypothesized that a better understanding of mechanisms involved in growth factor induced upregulation of nutrient transport will have significant clinical implications in developing safe and innovative strategies to treat patients with short bowel syndrome and other malabsorptive states.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery and Bioengineering Study Section (SB)
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May, Michael K
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University of Rochester
Schools of Dentistry
United States
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Avissar, Nelly E; Sax, Harry C; Toia, Liana (2008) In human entrocytes, GLN transport and ASCT2 surface expression induced by short-term EGF are MAPK, PI3K, and Rho-dependent. Dig Dis Sci 53:2113-25
Sax, Harry C (2006) Specific nutrients in intestinal failure: one size fits no one. Gastroenterology 130:S91-2
Avissar, Nelly E; Toia, Liana; Sax, Harry C (2005) Epidermal growth factor and/or growth hormone induce differential, side-specific signal transduction protein phosphorylation in enterocytes. JPEN J Parenter Enteral Nutr 29:322-35; discussion 335-6
Ray, Edward C; Avissar, Nelly E; Salloum, Rabih et al. (2005) Growth hormone and epidermal growth factor upregulate specific sodium-dependent glutamine uptake systems in human intestinal C2BBe1 cells. J Nutr 135:14-8
Avissar, Nelly E; Ziegler, Thomas R; Toia, Liana et al. (2004) ATB0/ASCT2 expression in residual rabbit bowel is decreased after massive enterectomy and is restored by growth hormone treatment. J Nutr 134:2173-7
Ray, Edward C; Avissar, Nelly E; Vukcevic, Dubravka et al. (2003) Growth hormone and epidermal growth factor together enhance amino acid transport systems B(0,+) and A in remnant small intestine after massive enterectomy. J Surg Res 113:257-63
Jonas, Carolyn R; Gu, Li H; Nkabyo, Yvonne S et al. (2003) Glutamine and KGF each regulate extracellular thiol/disulfide redox and enhance proliferation in Caco-2 cells. Am J Physiol Regul Integr Comp Physiol 285:R1421-9
Ray, Edward C; Avissar, Nelly E; Vukcevic, Dubravka et al. (2003) Growth hormone and epidermal growth factor together enhance amino acid transport systems B0,+ and A in remnant small intestine after massive enterectomy. J Surg Res 115:164-70
Ray, Edward C; Avissar, Nelly E; Sax, Harry C (2002) Methods used to study intestinal nutrient transport: past and present. J Surg Res 108:180-90
Ray, Edward C; Avissar, Nelly E; Sax, Harry C (2002) Growth factor regulation of enterocyte nutrient transport during intestinal adaptation. Am J Surg 183:361-71

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