Intestinal adaptation is the process of modulated cell proliferation and differentiation, resulting in growth of intestinal mucosa, to preserve or enhance digestive and absorptive capabilities during different physiological and pathophysiological circumstances. This proposal will test the hypothesis that intestinal adaptation is regulated by interactions among peptide hormones and growth factors produced locally in intestine, or in other tissues, in response to nutrients or other stimuli. Epidermal growth factor (EGF), products of intestinal proglucagon (enteroglucagon, glucagon-like peptides I and II (GLP-I and II), insulin-like growth factor I (IGF-I) and growth hormone GH will be the focus of study. Synthesis and/or serum levels of these peptides in will be assessed in intestine, liver, pancreas, submaxillary gland and kidney of three different models of adaptation. The time course, magnitude and cellular sites of regulated peptide synthesis or secretion will be tested for correlations with adaptive growth of small intestine. Models will include hyperplastic adaptation to small bowel resection, adaptation to mucosal injury by arabinofuranosyl-cytosine (ara-C) and adaptation to fasting and refeeding. Direct testing of putative trophic peptides alone or in combination, at doses observed during adaptation, will then establish their actions and interactions in regulating mucosal growth or the synthesis and secretion of other trophic peptides. Enteral nutrients are important for adaptive growth of the mucosa of the small intestine but the precise mechanisms by which they act are nor defined. Single nutrients will be given to rats after proximal small bowel resection via an intragastric cannula and the remainder of nutrient requirements will be given parenterally. The effects of specific intragastric nutrients on local production of specific trophic peptides and mucosal growth will be defined. Replacement of individual nutrients by the trophic peptide(s) they stimulate will then establish the extent to which the peptides mediate nutrient effects on adaptation. These studies will provide definitive information relevant to the optimal nutrient regime for recovery from small bowel surgery in humans and to the therapeutic benefits of trophic peptides for stimulating adaptive growth of small bowel. Completion of this proposed combination of (i) a molecular approach to study trophic peptide synthesis by Northern hybridization and at a cellular level by in situ hybridization histochemistry (ii) and endocrinologic approach using radioimmunoassay, immunocytochemistry and biological testing and (iii) a physiologic approach to study mucosal growth in different models, will have implications for future studies of the roles of the peptides studied herein, as well as other hormones and growth factors, in situations of normal and abnormal intestinal function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Kechele, Daniel O; Blue, R Eric; Zwarycz, Bailey et al. (2017) Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation. J Clin Invest 127:593-607
Andres, Sarah F; Santoro, M Agostina; Mah, Amanda T et al. (2015) Deletion of intestinal epithelial insulin receptor attenuates high-fat diet-induced elevations in cholesterol and stem, enteroendocrine, and Paneth cell mRNAs. Am J Physiol Gastrointest Liver Physiol 308:G100-11
Van Landeghem, Laurianne; Santoro, M Agostina; Mah, Amanda T et al. (2015) IGF1 stimulates crypt expansion via differential activation of 2 intestinal stem cell populations. FASEB J 29:2828-42
Poindexter, Shenika V; Reddy, Vishruth K; Mittal, Mukul K et al. (2015) Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury. Am J Physiol Gastrointest Liver Physiol 308:G562-71
Santoro, M Agostina; Blue, R Eric; Andres, Sarah F et al. (2015) Obesity and intestinal epithelial deletion of the insulin receptor, but not the IGF 1 receptor, affect radiation-induced apoptosis in colon. Am J Physiol Gastrointest Liver Physiol 309:G578-89
Mah, Amanda T; Van Landeghem, Laurianne; Gavin, Hannah E et al. (2014) Impact of diet-induced obesity on intestinal stem cells: hyperproliferation but impaired intrinsic function that requires insulin/IGF1. Endocrinology 155:3302-14
Santoro, M Agostina; Andres, Sarah F; Galanko, Joseph A et al. (2014) Reduced insulin-like growth factor I receptor and altered insulin receptor isoform mRNAs in normal mucosa predict colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 23:2093-100
Andres, Sarah F; Simmons, James G; Mah, Amanda T et al. (2013) Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation. J Cell Sci 126:5645-56
Hamilton, Kathryn E; T├ętreault, Marie-Pier; Lund, P Kay (2013) Opportunities and challenges for women PhD investigators in gastrointestinal research. Gastroenterology 145:266-71
Van Landeghem, Laurianne; Santoro, M Agostina; Krebs, Adrienne E et al. (2012) Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation. Am J Physiol Gastrointest Liver Physiol 302:G1111-32

Showing the most recent 10 out of 45 publications