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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711748
• 关键词: Cross; Talk; between; Endothelial; Cell

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.

理由：胰岛是高度血管化的，并包含一个独特的毛细管网络，其中每个细胞都与内皮细胞（EC）相近。 ECS产生正常细胞功能的启发性信号，以响应饮食中的葡萄糖和脂肪产生胰岛素来维持代谢稳态。但是，尚不清楚ECS如何影响细胞功能的潜在机制。 刺猬相互作用的蛋白质（HHIP）被发现是所有3种刺猬（HH）配体的推定拮抗剂。充当诱饵受体，全长HHOP及其分泌形式（SHHOP）都可以结合HH配体以调节其生物活性。可以确定的是，对胰岛的适当胰腺发育和正常细胞功能至关重要。然而，胰岛中的HHIP基因调节，分泌和裂解/脱落的精确机制知之甚少。最近，我们在正常胰岛中绘制了HHIP表达模式。我们的初步数据表明，HHIP可以在维持正常胰岛功能时介导EC和 - 细胞之间的串扰。 目标是3个目标： 目的1。定义EC中HHIP基因表达的分子调节。 目的2。阐明ECS-Origin Hop脱落/裂解的机理，以贡献Shhop形成的贡献； 目标3。研究HHIP/SHHOP在介导EC和 - 细胞之间介导正常胰岛功能中的串扰中的作用。 意义：我们的NSERC研究计划结合了分子和细胞方法，将在生理条件下的胰岛中介导ECS和 - 细胞之间的交叉讲话时，可以更好地了解HHIP/SHHOP调节机制。该NSERC计划还为我们的实验室中的HQP提供了高水平的多学科培训。