Reference number : GC-2017-Q1-02762, amendment number : , agreement type : G, recipient legal name : zhang, shao-ling (Université de Montréal), recipient country : CA, recipient province : nan, recipient city : Quebec|Québec, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : Rationale : Pancreatic islets are highly vascularized and contain a unique capillary network where each &beta;-cell is in cellular proximity to endothelial cell (EC). ECs produce instructive signals necessary for normal &beta; cell function in response to dietary glucose and fats to produce insulin for maintaining the metabolic homeostasis. However, the underlying mechanism of how ECs influence &beta;-cell function is not well understood. 
The hedgehog interacting protein (Hhip) was discovered as a putative antagonist of all 3 hedgehog (Hh) ligands. Acting as a decoy receptor, both full-length Hhip and its secreted form (sHhip) can bind Hh ligands to modulate their bio-activities. It is established that tight regulation of Hhip gene expression is essential for proper pancreas development and normal &beta;-cell function in matured islets. However, the precise mechanism(s) of Hhip gene regulation, secretion and cleavage/shedding in pancreatic islets are poorly understood. Recently, we have mapped Hhip expression pattern in normal islets&mdash;e.g., mainly detected in ECs, a little in &beta;-cells and none in &alpha;-cells. Our preliminary data suggested that Hhip might mediate a cross-talk between ECs and &beta;-cells in maintaining normal islet&rsquo;s function. 
 
 Objectives &amp; Hypothesis &amp; Aims : By using both cellular and animal models, we aim to establish an NSERC-funded research program to understand the complex regulatory mechanisms of Hhip gene expression and shedding implicating the cross-talk between ECs and &beta;-cells in islets in physiological conditions such as response dietary glucose and fats to produce insulin. We hypothesize that ECs-origin Hhip/sHhip might impact on &beta;-cell morphological changes/function via an autocrine/paracrine manner. We will test our hypothesis in 3 Aims: 
 
 Aim 1 . To define the molecular regulation of Hhip gene expression in ECs. 
 Aim 2 . To elucidate the mechanism of ECs-origin Hhip shedding/cleavage in contribution of sHhip formation; 
 Aim 3 . To investigate the role of Hhip/sHhip in mediating a cross-talk between ECs and &beta;-cells in maintaining normal islet&rsquo;s function. 
 
 Significance : Our NSERC research program combining both molecular and cellular approaches will provide a better understanding of Hhip/sHhip regulatory mechanisms in mediating the cross-talk between ECs and &beta;-cells in pancreatic islets in physiological conditions. This NSERC program also provides high level, multidisciplinary training to HQP in our lab., program purpose french : Rationale : Pancreatic islets are highly vascularized and contain a unique capillary network where each &beta;-cell is in cellular proximity to endothelial cell (EC). ECs produce instructive signals necessary for normal &beta; cell function in response to dietary glucose and fats to produce insulin for maintaining the metabolic homeostasis. However, the underlying mechanism of how ECs influence &beta;-cell function is not well understood. 
The hedgehog interacting protein (Hhip) was discovered as a putative antagonist of all 3 hedgehog (Hh) ligands. Acting as a decoy receptor, both full-length Hhip and its secreted form (sHhip) can bind Hh ligands to modulate their bio-activities. It is established that tight regulation of Hhip gene expression is essential for proper pancreas development and normal &beta;-cell function in matured islets. However, the precise mechanism(s) of Hhip gene regulation, secretion and cleavage/shedding in pancreatic islets are poorly understood. Recently, we have mapped Hhip expression pattern in normal islets&mdash;e.g., mainly detected in ECs, a little in &beta;-cells and none in &alpha;-cells. Our preliminary data suggested that Hhip might mediate a cross-talk between ECs and &beta;-cells in maintaining normal islet&rsquo;s function. 
 
 Objectives &amp; Hypothesis &amp; Aims : By using both cellular and animal models, we aim to establish an NSERC-funded research program to understand the complex regulatory mechanisms of Hhip gene expression and shedding implicating the cross-talk between ECs and &beta;-cells in islets in physiological conditions such as response dietary glucose and fats to produce insulin. We hypothesize that ECs-origin Hhip/sHhip might impact on &beta;-cell morphological changes/function via an autocrine/paracrine manner. We will test our hypothesis in 3 Aims: 
 
 Aim 1 . To define the molecular regulation of Hhip gene expression in ECs. 
 Aim 2 . To elucidate the mechanism of ECs-origin Hhip shedding/cleavage in contribution of sHhip formation; 
 Aim 3 . To investigate the role of Hhip/sHhip in mediating a cross-talk between ECs and &beta;-cells in maintaining normal islet&rsquo;s function. 
 
 Significance : Our NSERC research program combining both molecular and cellular approaches will provide a better understanding of Hhip/sHhip regulatory mechanisms in mediating the cross-talk between ECs and &beta;-cells in pancreatic islets in physiological conditions. This NSERC program also provides high level, multidisciplinary training to HQP in our lab., agreement title english : A Cross-Talk between Endothelial Cell and Beta-Cell in Pancreatic Islets: Role of Hedgehog Interacting Protein (Hhip), agreement title french : A Cross-Talk between Endothelial Cell and Beta-Cell in Pancreatic Islets: Role of Hedgehog Interacting Protein (Hhip), agreement number : RGPIN, agreement value : 140000.0, 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