Emergent Multi-Cellular Properties Regulating Pancreatic Islet Function

调节胰岛功能的新兴多细胞特性

基本信息

批准号：
10211854
负责人：
Richard KP Benninger
金额：
$ 34.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10211854
关键词：
Ablation Activities of Daily Living Acute Address Affect Beta Cell Blood Glucose Cells Cessation of life Characteristics Communication Computer Models Coupling Cyclic AMP Dependence Diabetes Mellitus Drug Targeting Endocrine Environment Failure Functional disorder Funding Gap Junctions Glucagon Glucose Goals Heterogeneity Human Image Imaging Device Immunofluorescence Immunologic Insulin Islet Cell Islets of Langerhans Knowledge Lasers Mediating Metabolic Modeling Mus Pancreas Pathogenicity Permeability Pharmacology Phase Phenotype Population Population Heterogeneity Preparation Preventive treatment Property Regulation Reporter Research Role Slice System Testing blood glucose regulation design diabetogenic experimental study insulin regulation insulin secretion islet mouse model pancreatic islet function programs recruit response small molecule therapeutic target tool

项目摘要

Diabetes is caused by insufficient secretion of insulin and subsequent loss of glucose homeostasis as a result of dysfunction or death of insulin-secreting β-cells. β-cells within the islet do not function autonomously: extensive interactions occur between β-cells and with other endocrine cells that control the regulation of insulin secretion. Previously, we and others established a critical role for gap-junction mediated electrical communication between β-cells that coordinates the dynamics of electrical activity, [Ca2+] elevations and insulin release. β-cells are functionally heterogenous, yet the way in which different populations of β-cells influence the function of the whole islet is poorly understood. As such, the overall goal of our research program is to understand how islet function is determined by coupling between the diverse populations of β-cells. In the previous funding period, we discovered and characterized distinct sub-populations of β-cells within the intact islet, that can influence the dynamics and glucose sensitivity of whole islet electrical activity. However critical gaps in our understanding remain. This includes how functional sub-populations impact both first phase and second phase dynamics of insulin secretion; the presence and role of functional sub-populations in human islets; and how changes in sub-populations in diabetes impact islet function. To address these open questions, we have designed 3 specific aims to test our overall hypothesis: that populations of β-cells with distinct functional characteristics exert disproportionate control over multiple aspects of the islet [Ca2+] response, via electrical coupling. 1) Characterize how β-cell sub-populations coordinate the initial first-phase response of the islet following glucose elevation; 2) Characterize the presence of functional sub-populations and electrical communication in human islets insitu; 3) Determine how conditions associated with type2 diabetes impact functional sub-populations and islet responsiveness. By understanding how heterogenous β-cell populations within the islet interact, we will gain fundamental understanding how islet electrical and insulin secretion response is regulated. Thus, therapeutic targets which may disproportionately influence a certain β-cell population may provide new ways to control the islet under pathogenic conditions.

糖尿病是由于胰岛素的分泌不足以及随后由于功能障碍或胰岛素分泌β细胞死亡而导致的葡萄糖稳态丧失引起的。胰岛内的β细胞不自主发挥作用：β细胞之间发生了广泛的相互作用，并且与控制调节胰岛素分泌的其他内分泌细胞之间发生了广泛的相互作用。以前，我们和其他人在间隙结构介导的β细胞之间介导的电气通信方面建立了关键作用，β细胞协调电活动的动力学，[Ca2+]升高和胰岛素释放。 β细胞在功能上是异质的，但是不同β细胞影响整个胰岛功能的方式却鲜为人知。因此，我们的研究计划的总体目标是了解如何通过β细胞的潜水员种群之间的耦合来确定胰岛功能。在上一个资金期间，我们发现并表征了完整胰岛内β细胞的不同亚种群，从而影响整个胰岛电活动的动力学和葡萄糖敏感性。但是，我们的理解中的关键差距仍然存在。这包括胰岛素分泌的第一阶段和第二阶段动力学的功能子群如何影响；功能亚群在人类胰岛中的存在和作用；以及糖尿病中亚人群的变化如何影响胰岛功能。为了解决这些开放的问题，我们设计了3个特定旨在测试我们的总体假设：具有独特功能特征的β细胞种群对胰岛的多个方面[Ca2+]响应的多个方面的控制不成比例。耦合。 1）表征β细胞亚群如何协调葡萄糖升高后胰岛的初始第一阶段响应； 2）表征人类胰岛中的功能亚群和电通通信的表征； 3）确定与2型糖尿病相关的条件如何影响功能亚人群和胰岛响应能力。通过了解胰岛中的异质β细胞种群如何相互作用，我们将获得基本了解胰岛电和胰岛素分泌反应的基本。这是，可能不成比例地影响特定β细胞种群的治疗靶标可能会提供新的方法来控制致病条件下的胰岛。