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

胰岛内皮细胞和 β 细胞之间的交叉对话：刺猬相互作用蛋白 (Hhip) 的作用

• 批准号: RGPIN-2017-05615
• 负责人: zhang, shaoling
• 金额: $ 2.04万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=669708
• 关键词: Cross; Talk; between; Endothelial; Cell

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.

原理：胰岛高度血运丰富，包含一个独特的毛细血管网络，其中每个β细胞都在细胞内靠近内皮细胞(EC)。内皮细胞产生正常的β细胞功能所需的有益信号，以响应饮食中的葡萄糖和脂肪，产生维持代谢平衡的胰岛素。然而，内皮细胞如何影响β-细胞功能的潜在机制尚不清楚。*刺猬相互作用蛋白(HHIP)被发现是所有3种刺猬(HH)配体的拮抗剂。作为一种诱饵受体，全长HHIP及其分泌型(SHHIP)都能与HH配体结合，调节其生物活性。已证实HHIP基因表达的严格调控对于成熟胰岛的正常胰腺发育和正常的β细胞功能是必不可少的。然而，HHIP基因在胰岛中的调控、分泌和分裂/脱落的确切机制(S)却知之甚少。最近，我们已经定位了HHIP在正常胰岛中的表达模式--例如，主要在ECs中检测到，少量在β细胞中检测到，在α细胞中没有检测到。我们的初步数据表明，HHIP可能在维持正常胰岛功能的过程中介导了ECs和β-细胞之间的相互作用。*目的：通过使用细胞和动物模型，我们的目标是建立一个由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，该机制涉及胰岛中ECs和β-细胞在生理条件下(如响应饮食中的葡萄糖和脂肪以产生胰岛素)之间的相互作用。我们推测内皮细胞来源的HHIP/SHIP可能通过自分泌/旁分泌方式影响β细胞的形态变化/功能。我们将从三个方面验证我们的假设：*目的1.确定HHIP基因在内皮细胞中表达的分子调控.*目的2.阐明内皮细胞起源的HHIP脱落/切割在sHHIP形成中的作用机制；*目的3.探讨HHIP/SHIP在维持正常胰岛功能中介导ECs和β-细胞之间的串扰中的作用。*意义：我们的NSERC研究项目结合了分子和细胞的方法，将更好地了解HHIP/SSHIP在生理条件下调节ECs和β-细胞之间的串扰的机制。该NSERC项目还为我们实验室的HQP提供高水平的多学科培训。