Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Rationale : Pancreatic islets are highly vascularized and contain a unique capillary network where each β-cell is in cellular proximity to endothelial cell (EC). ECs produce instructive signals necessary for normal β 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 β-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 β-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—e.g., mainly detected in ECs, a little in β-cells and none in α-cells. Our preliminary data suggested that Hhip might mediate a cross-talk between ECs and β-cells in maintaining normal islet’s function.

Objectives & Hypothesis & 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 β-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 β-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 β-cells in maintaining normal islet’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 β-cells in pancreatic islets in physiological conditions. This NSERC program also provides high level, multidisciplinary training to HQP in our lab.