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

原理：胰岛是高度血管化的，包含一个独特的毛细血管网络，其中每个β细胞靠近内皮细胞（EC）。ECs产生正常β细胞功能所必需的指导性信号，以响应饮食中的葡萄糖和脂肪来产生胰岛素以维持代谢稳态。然而，内皮细胞如何影响β细胞功能的潜在机制尚不清楚。***刺猬相互作用蛋白（hip）被发现是所有3种刺猬（Hh）配体的推定拮抗剂。全长Hhip及其分泌形式（ship）均可作为诱饵受体，结合Hh配体调节其生物活性。研究表明，hip基因表达的严格调控对成熟胰岛胰腺的正常发育和β细胞的正常功能至关重要。然而，hip基因在胰岛中的调控、分泌和裂解/脱落的确切机制尚不清楚。最近，我们绘制了正常胰岛中hip的表达模式。，主要在ECs中检测到，β-细胞中少量检测到，α-细胞中无检测到。我们的初步数据表明，hip可能介导内皮细胞和β细胞之间的串扰，以维持正常的胰岛功能。******目的与假设与目的：通过细胞和动物模型，我们旨在建立一个nserc资助的研究项目，以了解在生理条件下胰岛ec和β-细胞之间的相互作用，如饮食葡萄糖和脂肪产生胰岛素的表达和脱落的复杂调控机制。我们假设ec来源的hip/ ship可能通过自分泌/旁分泌的方式影响β细胞的形态变化/功能。我们将在3个目标中检验我们的假设：******目标1。目的：明确hip基因在ECs中表达的分子调控。* * *的目标2。阐明ECs-origin - hip -脱落/裂解在船舶形成中的作用机制；* * *的目标3。探讨hip/ ship介导内皮细胞与β-细胞间的串扰在维持正常胰岛功能中的作用。******意义：我们的NSERC研究计划结合分子和细胞方法，将更好地了解在生理条件下胰岛中介导ECs和β-细胞之间的串话的hip/ ship调节机制。这个NSERC项目还为我们实验室的HQP提供了高水平的多学科培训。

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.