A Cross-Talk between Endothelial Cell and Beta-Cell in Pancreatic Islets: Role of Hedgehog Interacting Protein (Hhip)

点击翻译按钮获取中文摘要

Rationale: Pancreatic islets are highly vascularized and contain a unique capillary network where each -cell is in cellular proximity to endothelial cell (EC). ECs produce instructive signals necessary for normal 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 -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 -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 isletse.g., mainly detected in ECs, a little in -cells and none in -cells. Our preliminary data suggested that Hhip might mediate a cross-talk between ECs and -cells in maintaining normal islet's function. Objectives sis 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 -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 -cells in pancreatic islets in physiological conditions. This NSERC program also provides high level, multidisciplinary training to HQP in our lab.