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.

糖尿病是由胰岛素分泌不足以及随后由于胰岛内分泌胰岛素的 β 细胞功能障碍或死亡而导致的葡萄糖稳态丧失引起的：β 细胞之间以及与其他细胞之间发生广泛的相互作用。此前，我们和其他人确定了 β 细胞之间间隙连接介导的电通讯的关键作用，协调电活动、[Ca2+] 升高和胰岛素的动态。 β细胞在功能上是异质的，但不同群体的β细胞影响整个胰岛功能的方式却知之甚少，因此，我们研究项目的总体目标是了解胰岛功能是如何决定的。在之前的资助期间，我们发现并表征了完整胰岛内不同的 β 细胞亚群，它们可以影响整个胰岛电活动的动力学和葡萄糖敏感性。在我们的理解中仍然存在。包括功能亚群如何影响胰岛素分泌的第一阶段和第二阶段动态；功能亚群在人类胰岛中的存在和作用；以及糖尿病亚群的变化如何影响胰岛功能。我们设计了 3 个具体目标来检验我们的总体假设：具有不同功能特征的 β 细胞群通过电对胰岛 [Ca2+] 反应的多个方面发挥不成比例的控制 1) 表征 β 细胞亚群如何协调血糖升高后胰岛的初始第一阶段反应；2) 表征人类胰岛中功能亚群的存在和电通讯；3) 确定相关条件。 2 型糖尿病影响功能亚群和胰岛反应性通过了解胰岛内异质 β 细胞群如何相互作用，我们将基本了解胰岛电和胰岛素分泌反应是如何调节的。可能不成比例地影响某些β细胞群的治疗靶标可能提供在致病条件下控制胰岛的新方法。