Despite considerable recent interest, the mechanisms of intestinal adaptation following resection remain incompletely defined. While a variety of luminal and neuroendocrine stimuli probably play a role in this response, the hypothesis underlying this application is that the recently identified gut hormone glucagon-like peptide-2 (GLP-2) is a principal mediator and as such has considerable potential for clinical use in the treatment of disorders where mucosal growth is desireable, such as short bowel syndrome, parenteral nutrition-induced intestinal atrophy, and in the setting of intestinal injury. To begin to test this hypothesis, this application proposes a series of experiments designed to more fully characterize GLP-2, both in terms of its physiologic effects and its efficacy in several models of human disease. To this end, we plan to pursue the following specific aims: 1. To identify the cellular mechanisms of GLP-2's intestinotrophic effects. 2. To determine the other effects of GLP-2 on the gastrointestinal epithelium. 3. To examine the physiologic role and therapeutic potential of GLP-2 in intestinal adaptation and repair. The successful completion of these experiments should provide new insights into not only the actions of GLP-2, but also the mechanisms of intestinal growth and regeneration. We anticipate that the results of these studies will provide a basis for further clinical trials designed to test the therapeutic potential of GLP-2 in human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047326-09
Application #
6524189
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
May, Michael K
Project Start
1994-08-15
Project End
2004-09-29
Budget Start
2002-09-30
Budget End
2003-09-29
Support Year
9
Fiscal Year
2002
Total Cost
$225,792
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Waseem, Talat; Duxbury, Mark; Ashley, Stanley W et al. (2014) Ghrelin promotes intestinal epithelial cell proliferation through PI3K/Akt pathway and EGFR trans-activation both converging to ERK 1/2 phosphorylation. Peptides 52:113-21
Balakrishnan, Anita; Stearns, Adam T; Ashley, Stanley W et al. (2012) PER1 modulates SGLT1 transcription in vitro independent of E-box status. Dig Dis Sci 57:1525-36
Balakrishnan, Anita; Tavakkolizadeh, Ali; Rhoads, David B (2012) Circadian clock genes and implications for intestinal nutrient uptake. J Nutr Biochem 23:417-22
Balakrishnan, Anita; Stearns, Adam T; Park, Peter J et al. (2012) Upregulation of proapoptotic microRNA mir-125a after massive small bowel resection in rats. Ann Surg 255:747-53
Stearns, Adam T; Balakrishnan, Anita; Rhoads, David B et al. (2010) Rapid upregulation of sodium-glucose transporter SGLT1 in response to intestinal sweet taste stimulation. Ann Surg 251:865-71
Balakrishnan, Anita; Stearns, Adam T; Park, Peter J et al. (2010) MicroRNA mir-16 is anti-proliferative in enterocytes and exhibits diurnal rhythmicity in intestinal crypts. Exp Cell Res 316:3512-21
Balakrishnan, Anita; Stearns, Adam T; Ashley, Stanley W et al. (2010) Restricted feeding phase shifts clock gene and sodium glucose cotransporter 1 (SGLT1) expression in rats. J Nutr 140:908-14
Stearns, Adam T; Balakrishnan, Anita; Rhoads, David B et al. (2009) Diurnal expression of the rat intestinal sodium-glucose cotransporter 1 (SGLT1) is independent of local luminal factors. Surgery 145:294-302
Balakrishnan, Anita; Stearns, Adam T; Rhoads, David B et al. (2008) Defining the transcriptional regulation of the intestinal sodium-glucose cotransporter using RNA-interference mediated gene silencing. Surgery 144:168-73
Stearns, Adam T; Balakrishnan, Anita; Rhoads, David B et al. (2008) Diurnal rhythmicity in the transcription of jejunal drug transporters. J Pharmacol Sci 108:144-8

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