Emergent Multi-Cellular Properties Regulating Pancreatic Islet Function

调节胰岛功能的新兴多细胞特性

• 批准号: 10617323
• 负责人: Richard KP Benninger
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617323
• 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; Experimental Models; Failure; Functional disorder; Funding; Gap Junctions; Glucagon; Glucose; Goals; Heterogeneity; Human; Image; Imaging Device; Immunofluorescence Immunologic; In Situ; Insulin; Islets of Langerhans; Knowledge; Lasers; Mediating; Metabolic; Modeling; Mus; Pancreas; Pathogenicity; Permeability; 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; pharmacologic; programs; recruit; response; small molecule; therapeutic target; tool

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 the gap junction dependence for functional sub-populations under healthy conditions and in type2 diabetes. 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和随后的葡萄糖稳态丧失引起的。 由于分泌胰岛素的β细胞功能障碍或死亡。β-中的单元格 胰岛功能不是自主的：β细胞之间以及与其他细胞之间发生广泛的相互作用 控制胰岛素分泌调节的内分泌细胞。此前，我们和其他人 确立了缝隙连接介导的电子通信的关键作用 在协调电活动、钙升高和胰岛素动态的β细胞之间 放手。β-细胞在功能上是不同的，但不同群体的 β细胞对整个胰岛功能的影响还知之甚少。因此， 我们研究计划的总体目标是了解胰岛功能是如何决定的 通过在不同的β细胞群体之间进行耦合。在上一个资助期，我们 在完整的胰岛内发现并表征了不同的β细胞亚群，这可以 影响整个胰岛电活动的动力学和葡萄糖敏感性。不管多么关键 我们在理解上的差距仍然存在。这包括功能子群体如何首先对两者产生影响 胰岛素分泌的时相和第二时相动力学；功能性的存在和作用 人类胰岛中的亚群；糖尿病亚群的变化对胰岛的影响 功能。为了解决这些悬而未决的问题，我们设计了3个具体目标来测试我们的整体 假设：具有不同功能特征的β细胞群体 不成比例地控制胰岛钙反应的多个方面，通过电子 耦合。1)描述β细胞亚群如何协调初始第一阶段 胰岛在血糖升高后的反应；2)表征 人原位胰岛的功能亚群和电通讯；3)决定 健康条件下和2型功能亚群对缝隙连接的依赖性 糖尿病。通过了解胰岛内异种β细胞群体是如何相互作用的，我们将 从根本上了解胰岛电和胰岛素分泌反应是如何调节的。 因此，可能不成比例地影响特定β细胞的治疗靶点 种群可能为控制病原性条件下的胰岛提供新的途径。