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

基本原理：胰岛是高度血管化的，并且含有独特的毛细血管网络，其中每个细胞与内皮细胞（EC）细胞接近。EC产生正常细胞功能所需的指示信号，以响应饮食葡萄糖和脂肪，从而产生胰岛素以维持代谢稳态。然而，内皮细胞如何影响细胞功能的潜在机制还没有很好地理解。 刺猬相互作用蛋白（Hhip）被发现是所有3种刺猬（Hh）配体的假定拮抗剂。作为诱饵受体，全长Hhip及其分泌形式（sHhip）都可以结合Hh配体以调节其生物活性。已经确定Hhip基因表达的严格调节对于成熟胰岛中适当的胰腺发育和正常细胞功能是必不可少的。然而，Hhip基因在胰岛中的调节、分泌和切割/脱落的精确机制知之甚少。最近，我们绘制了正常胰岛中Hip的表达模式，主要在内皮细胞中检测到，细胞内检测到少量，细胞内检测不到。我们的初步数据表明，Hip可能介导的细胞和细胞之间的串扰在维持正常的胰岛功能。 目标分为三个目标： 目标1。目的探讨内皮细胞中Hip基因表达的分子调控机制。 目标2.阐明内皮细胞来源的Hip脱落/裂解在sHip形成中的作用机制; 目标3。目的探讨Hip/sHip介导的内皮细胞与胰岛β细胞间的相互作用对维持正常胰岛功能的作用。 重要性：我们的NSERC研究计划结合分子和细胞的方法将提供一个更好的理解HHip/sHHip调节机制，在介导的EC和细胞之间的串扰在胰岛在生理条件下。这个NSERC计划还提供了高水平的，多学科的培训，以HQP在我们的实验室。

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.