Regulation of spatial organization and cell-cell communication in the islet of Langerhans

朗格汉斯岛空间组织和细胞间通讯的调节

基本信息

批准号：
10427288
负责人：
Barak Blum
金额：
$ 38.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427288
关键词：
3-Dimensional Affect Alpha Cell Amelia Architecture Beta Cell Binding Biomedical Engineering Cadaver Cadherins Cell Adhesion Cell Adhesion Molecules Cell Communication Cell Death Cell Maturation Cell Separation Cell Surface Proteins Cell Survival Cell physiology Cell-Adhesion Molecule Receptors Cell-Cell Adhesion Cells Clinical Collaborations Coupling Cytoskeleton D Cells Data Defect Deterioration Development Diabetes Mellitus Down-Regulation Drug Targeting Endocrine Exhibits F-Actin Financial compensation Foundations Functional disorder Generations Glucagon Glucose Glucose Intolerance Goals Growth Hormonal Hormone secretion Hormones Human Impairment In Vitro Insulin Insulin Resistance Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Letters Ligands Link Mediating Methods Mus Nutritional Obesity Pharmacology Phase Phenotype Process Proteins Receptor Signaling Regulation Reporting Research Rodent Role Signal Pathway Signal Transduction Source Stimulus Testing Type 2 diabetic Visualization Work axon guidance blood glucose regulation cell motility cell type diabetic endocrine pancreas development extracellular glucose tolerance hormone regulation human pluripotent stem cell impaired glucose tolerance in vivo insulin secretion islet link protein preservation prevent receptor receptor function response scaffold transcriptome sequencing transdifferentiation vesicle transport

项目摘要

Coordinated hormone secretion from the different endocrine cell types in the islets of Langerhans is critical to glucose homeostasis. Spatial islet organization and cell-cell communication are disrupted in obesity, insulin resistance and diabetes, leading to loss of coordinated hormone regulation. Despite the critical roles of islet organization and cell-cell communication in islet function, drugs that target them as potential therapies to diabetes have not yet been developed. Roundabout (Robo) receptors are cell adhesion proteins expressed in the islet. Robo receptors can link cell-cell contact to cytoskeleton dynamic and vesicle transport in insulin secretion. The expression Robo in the islets of mice and humans are severely diminished in obesity and diabetes. We have recently found that deletion of Robo1 and Robo2 in beta cells in mice results in loss of islet organization and impaired glucose tolerance. We further demonstrated that the islet phenotype seen upon beta cell-selective deletion of Robo is not due to transdifferentiation of beta cells to alpha or delta cells, nor is it the result of loss of beta cell maturation or beta cell death. Rather, our results led us to hypothesize that expression of Robo in beta cells facilitates correct islet organization which is required for endocrine cell-cell communication and correct glucose response. According to this hypothesis, the downregulation of Robo in obesity disrupts islet organization, leading to loss of cell-cell communication, thus contributing to dysfunctional glucose response. Understanding how expression of Robo in beta cells regulates islet organization and hormone secretion will provide the basis for new pharmacological approaches to diabetes. We will test the above hypothesis with two specific aims: in Aim 1, we will test the hypothesis that deletion of Robo in beta cells impairs insulin and glucagon secretion. We will further test the hypothesis that deletion of Robo disrupts functional beta cell-beta cell coupling using intravital visualization of synchronized insulin secretion. We will also test the hypothesis that Robo regulates hormone secretion through mediating endocrine cell-cell adhesion. In Aim 2, we will determine how expression of Robo in beta cells controls islet organization, and determine the involvement of the Robo ligand, Slit, in this process. We will further identify signaling pathways and downstream Robo targets in beta cells which could account for the defects in islet organization and glucose tolerance. These data will have important impact on diabetes in three translational aspects: 1) Robo signaling may be manipulated to prevent and restore the deterioration in islet organization and endocrine cell-cell communication in type-2 diabetics; 2) Robo signaling may be used to confer correct 3D organization and cell-cell contact in human pluripotent stem cells-derived islet-like clusters in vitro, to generate an unlimited source of bona fide islets for transplantation, and 3) Robo receptors and their extracellular ligand, Slit, may be used in bioengineering approaches for developing matrix scaffolds that could support structural integrity, survival and function in cadaver islets in clinical islet transplantation settings.

兰格汉胰岛中不同内分泌细胞类型中的激素分泌对于葡萄糖稳态至关重要。空间胰岛组织和细胞 - 细胞通信在肥胖，胰岛素抵抗和糖尿病中受到破坏，从而导致丧失协调的激素调节。尽管胰岛组织和细胞 - 细胞通信在胰岛功能中的关键作用，但尚未开发针对糖尿病的潜在疗法的药物。回旋处（ROBO）受体是在胰岛中表达的细胞粘附蛋白。机器人受体可以将细胞细胞接触与胰岛素分泌中的细胞骨架动态和囊泡转运联系起来。小鼠和人类胰岛中的表达机器人在肥胖和糖尿病中严重减少。我们最近发现，小鼠β细胞中ROBO1和ROBO2的删除会导致胰岛组织的丧失和葡萄糖耐受性受损。我们进一步证明，在Beta细胞选择性缺失Robo时看到的胰岛表型并不是由于β细胞向α或三角洲细胞的转分化，也不是由于β细胞成熟或β细胞死亡丧失的结果。相反，我们的结果导致我们假设在β细胞中Robo的表达促进了正确的胰岛组织，这是内分泌细胞 - 细胞通信和正确葡萄糖反应所必需的。根据这一假设，肥胖症中机器人的下调破坏了胰岛组织，导致细胞 - 细胞通信的丧失，从而导致功能障碍的葡萄糖反应。了解β细胞中机器人的表达如何调节胰岛组织和激素分泌将为新的糖尿病药理方法提供基础。我们将以两个具体的目的检验上述假设：在AIM 1中，我们将测试β细胞中Robo删除的假设会损害胰岛素和胰高血糖素的分泌。我们将进一步检验以下假设：ROBO的缺失使用同步胰岛素分泌的静脉内可视化破坏功能性β细胞-BetA细胞偶联。我们还将测试通过介导内分泌细胞粘附来调节激素分泌的假设。在AIM 2中，我们将确定Robo在Beta细胞中的表达如何控制胰岛组织，并确定在此过程中的Robo配体Slit的参与。我们将进一步识别β细胞中的信号通路和下游机器人目标，这可以解释胰岛组织和葡萄糖公差的缺陷。这些数据将对三个转化方面的糖尿病产生重要影响：1）可以操纵机器人信号传导，以防止和恢复2型糖尿病患者胰岛组织和内分泌细胞 - 细胞通信的恶化； 2）可以使用机器人信号传导在人类多能干细胞衍生的胰岛样群中进行校正3D组织和细胞电池接触体外，以产生无限的善意胰岛来源来移植，3）机器人受体及其在细胞外辅助上的构建和构造量的构建量群，以至于可以用来构建Matix and Inturolts Matix and Intruilt Matrix Insprive Insprix Insprix nightrix Insprots Inluctrix Insprots Inluctrix Insprotrix Insprolix Inscord Inluctrix intrix Inscord intrix nightrix cromboltix intrix nightrix。在临床胰岛移植设置中的尸体胰岛中。