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β细胞与内皮细胞（EC）细胞接近。EC响应于饮食葡萄糖和脂肪产生正常β细胞功能所必需的指导性信号，以产生用于维持代谢稳态的胰岛素。然而，内皮细胞如何影响β细胞功能的潜在机制尚未完全了解。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。已确定Hhip基因表达的严格调节对于成熟胰岛中的适当胰腺发育和正常β细胞功能是必需的。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，我们已经绘制了正常胰岛中Hhip表达模式-例如，主要在内皮细胞中检测到，β细胞中有少量，α细胞中无。我们的初步数据表明，Hip可能介导EC和β细胞之间的串扰，以维持正常的胰岛功能。** 目标和假设和目的：通过使用细胞和动物模型，我们的目标是建立一个NSERC资助的研究计划，以了解Hhip基因表达和脱落的复杂调控机制，这些机制涉及在生理条件下胰岛中EC和β细胞之间的串扰，例如响应饮食葡萄糖和脂肪以产生胰岛素。我们推测内皮细胞来源的Hip/sHip可能通过自分泌/旁分泌方式影响β细胞的形态学变化/功能。我们将在3个目标中测试我们的假设：* 目标1。目的：明确内皮细胞中Hip基因表达的分子调控。目标二。阐明EC来源的Hip脱落/切割对sHip形成的贡献的机制; * 目的3.探讨Hip/sHip介导内皮细胞与胰岛β细胞之间的相互作用，以维持正常胰岛功能。重要性：我们的NSERC研究计划结合了分子和细胞方法，将更好地了解Hhip/sHhip调节机制在生理条件下介导胰岛中EC和β细胞之间的串扰。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 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.