Reference number : GC-2017-Q1-02994, amendment number : , agreement type : G, recipient legal name : Mulvihill, Erin (University of Ottawa)|Mulvihill, Erin (Université d’Ottawa), recipient country : CA, recipient province : nan, recipient city : Ontario, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : Incretins and Nutrient Induced Plasticity 
 
The intestine is not a passive conduit but a large, dynamic organ which adjusts to large variations in both nutrient supply and energy demand. The structure of the mucosa undergoes robust adaptation as cellular processes including epithelial cell proliferation, apoptosis and differentiation may be downregulated with nutrient deprivation and recovered upon nutrient ingestion. As the gut is an energetically demanding organ, maintaining sufficient work capacity for nutrient absorption while offsetting metabolic cost is vital. Two incretin hormone peptides are secreted from enteroendocrine L cells and K cells respectively, glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) very rapidly post-prandially. GLP-1 and GIP each signal through a distinct G-protein coupled receptor, the GLP-1R and GIPR respectively and are classically thought to target the islet to increase glucose-stimulated insulin secretion. However, the incretin receptors are expressed throughout the gastrointestinal tract and the enteroendocrine cells which secrete GLP-1 and GIP are in direct contact with nutrients in the intestinal lumen, the microvasculature and nervous system making them ideally situated to mediate the highly adaptive response from a fasted to fed state. This proposal aims to identify and define novel signaling pathways through which the incretin hormones GIP and GLP-1 dynamically regulate the structure and function of the intestinal tract in response to ingested nutrients. 
 
Hypothesis: The gut derived incretin hormones, GLP-1 and GIP mediate intestinal nutrient-induced plasticity. 
Objectives: In order to define the mechanisms underlying the role of the incretin hormones for mediating nutrient induced plasticity, a number of key experiments are required. In Wildtype (WT) and Double Incretin Receptor Knock Out mice (DIRKO) littermate controls exposed to fasting or post-prandial conditions we will determine if: (a) morphological composition of the gut changes appropriately with feeding, (b) cell growth and differentiation of the epithelium, (c) the effect of incretin signaling on digestion and nutrient absorption, (d) apoptosis and proliferation of the gut epithelium, (e) if the expression levels and protein levels of key effectors required for fasting or refeeding blocked in mice in which the GLP-1R and GIPR have been deleted. 
 
The applicant has significant expertise with all of the techniques included in this proposal; therefore trainees will acquire a number of complementary and sophisticated tools/approaches for isolating cells and appropriate use of animals to apply to their future research programs. 
 
Expected Results and Relevance: We anticipate identifying a critical role for GIPR and GLP-1R signaling in mediating the adaptation of the small intestine to nutrient intake. 
 
 
 
R, program purpose french : Incretins and Nutrient Induced Plasticity 
 
The intestine is not a passive conduit but a large, dynamic organ which adjusts to large variations in both nutrient supply and energy demand. The structure of the mucosa undergoes robust adaptation as cellular processes including epithelial cell proliferation, apoptosis and differentiation may be downregulated with nutrient deprivation and recovered upon nutrient ingestion. As the gut is an energetically demanding organ, maintaining sufficient work capacity for nutrient absorption while offsetting metabolic cost is vital. Two incretin hormone peptides are secreted from enteroendocrine L cells and K cells respectively, glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) very rapidly post-prandially. GLP-1 and GIP each signal through a distinct G-protein coupled receptor, the GLP-1R and GIPR respectively and are classically thought to target the islet to increase glucose-stimulated insulin secretion. However, the incretin receptors are expressed throughout the gastrointestinal tract and the enteroendocrine cells which secrete GLP-1 and GIP are in direct contact with nutrients in the intestinal lumen, the microvasculature and nervous system making them ideally situated to mediate the highly adaptive response from a fasted to fed state. This proposal aims to identify and define novel signaling pathways through which the incretin hormones GIP and GLP-1 dynamically regulate the structure and function of the intestinal tract in response to ingested nutrients. 
 
Hypothesis: The gut derived incretin hormones, GLP-1 and GIP mediate intestinal nutrient-induced plasticity. 
Objectives: In order to define the mechanisms underlying the role of the incretin hormones for mediating nutrient induced plasticity, a number of key experiments are required. In Wildtype (WT) and Double Incretin Receptor Knock Out mice (DIRKO) littermate controls exposed to fasting or post-prandial conditions we will determine if: (a) morphological composition of the gut changes appropriately with feeding, (b) cell growth and differentiation of the epithelium, (c) the effect of incretin signaling on digestion and nutrient absorption, (d) apoptosis and proliferation of the gut epithelium, (e) if the expression levels and protein levels of key effectors required for fasting or refeeding blocked in mice in which the GLP-1R and GIPR have been deleted. 
 
The applicant has significant expertise with all of the techniques included in this proposal; therefore trainees will acquire a number of complementary and sophisticated tools/approaches for isolating cells and appropriate use of animals to apply to their future research programs. 
 
Expected Results and Relevance: We anticipate identifying a critical role for GIPR and GLP-1R signaling in mediating the adaptation of the small intestine to nutrient intake. 
 
 
 
R, agreement title english : Incretins and Nutrient induced Plasticity, agreement title french : Incretins and Nutrient induced Plasticity, agreement number : RGPIN, agreement value : 115000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada