Microfluidic Devices for Determining Dynamics of Islets of Langerhans

用于确定朗格汉斯岛动力学的微流体装置

• 批准号: 9914104
• 负责人: Michael Gabriel Roper
• 金额: $ 35.64万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914104
• 关键词: Affect; Behavior; Beta Cell; Biological Assay; Biological Process; Blood Glucose; Cells; Communication; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Drug Screening; Feedback; Frequencies; Glucagon; Glucose; Glutamates; Goals; Health; Hepatic; Hepatocyte; Hormonal; Hormone secretion; Hormones; Human; Hyperglycemia; In Vitro; Individual; Insulin; Islets of Langerhans; Knowledge; Laboratories; Lead; Literature; Liver; Measurement; Measures; Metabolic; Metabolic Diseases; Methods; Microfluidic Microchips; Microfluidics; Mission; Modeling; Monitor; Output; Pancreas; Pathogenesis; Perfusion; Periodicity; Phase; Physiologic pulse; Play; Portal vein structure; Prediabetes syndrome; Process; Public Health; Regulation; Reporting; Research; Role; Shapes; System; Technology; Testing; Therapeutic; Time; Type 2 diabetic; United States National Institutes of Health; Work; blood glucose regulation; design; diabetic; drug metabolism; gamma-Aminobutyric Acid; glucose metabolism; glucose monitor; glucose output; hormonal signals; improved; in vivo; innovation; insulin secretion; islet; liver metabolism; metabolic abnormality assessment; non-diabetic; novel strategies; pandemic disease; response; small molecule; temporal measurement; therapeutic development

The secretory dynamics of insulin and glucagon from individual pancreatic islets of Langerhans and the roles that these dynamics play in hepatic glucose regulation are unknown. The long-term goal of the Roper laboratory is to decode cellular communication to enable understanding of normal biological function and disease progression. The objective of this proposal is to identify the control mechanisms that regulate dynamic hormone release from islets and how dynamic hormone input to the liver optimizes net hepatic glucose control by the liver. The central hypothesis is that insulin and glucagon released from islets of Langerhans interact with the liver to generate a feedback loop that synchronizes islet behavior, sets the phase of the insulin and glucagon oscillations, and promotes optimal hepatic metabolism. The rationale for performing this work is that a thorough understanding of the dynamics of glucose-regulatory hormone secretion and glucose handling by the liver may lead to the design of therapeutic approaches that alleviate the complications associated with diabetes and other metabolic diseases. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the dynamics of glucose-regulatory hormone release from islets, 2) Identify the dynamics of small molecule secretion from islets that shape hormonal response, and 3) Identify the metabolic response of hepatocytes to dynamic hormonal profiles. Under the first aim, a novel approach to measure glucagon secretion from single islets with high temporal resolution will be utilized. This method will be incorporated with our assay for insulin release to enable hormone oscillation amplitudes, frequencies, and phase relationships to be identified. In the second aim, γ-aminobutyric acid and glutamate secretion will be monitored from islets simultaneously with insulin and glucagon secretion. This will enable the determination of the roles that these small molecules play in oscillatory hormone release. In the third aim, pulsatile hormone profiles will be delivered to hepatocytes while monitoring glucose output. This method will facilitate the understanding of how dynamic hormone profiles control hepatic behavior. The proposed research is innovative because the microfluidic systems and measurement approaches developed in this proposal will allow dynamics of islet and hepatocyte behavior to be observed for the first time. These results will provide a significant increase in the knowledge of the interplay between the pancreas and liver, which is crucial for fully understanding the mechanism of glucose homeostasis and how it goes awry in metabolic diseases. Ultimately, this knowledge has the potential to guide therapeutic development for reducing the problems associated with unregulated glucose levels in type II diabetics.

来自兰格汉（Langerhans）单个胰岛和角色的胰岛素和胰高血糖素的秘书动力学 这些动态在肝葡萄糖调节中发挥作用是未知的。绳索的长期目标 实验室是为了解码细胞通信，以了解正常的生物学功能和 疾病进展。该建议的目的是确定调节动态的控制机制 从胰岛释放马酮，以及肝脏对肝脏的动态输入如何优化净肝葡萄糖控制 肝脏。中心假设是从Langerhans胰岛释放的胰岛素和谷歌与 肝脏生成一个同步胰岛行为，设置胰岛素的相位的反馈回路和 胰高血糖素振荡并促进最佳的肝肝新陈代谢。执行这项工作的理由是 对通过 肝脏可能导致设计治疗方法的设计，以减轻与并发症相关的并发症 糖尿病和其他代谢疾病。在强大的初步数据的指导下，该假设将通过 追求三个特定目标：1）确定胰岛释放葡萄糖调节的动力学，2） 从塑造激素反应的胰岛中确定小分子分泌的动力学，3）确定 肝细胞对动态马雌性轮廓的代谢反应。在第一个目标下，一种新颖的方法 将利用具有高临时分辨率的单个胰岛的胰高血糖素分泌。这个方法将是 与我们的胰岛素释放评估合并，以实现激素振荡振幅，频率和 阶段关系要识别。在第二个目标中，γ-氨基丁酸和谷氨酸分泌将是 仅用胰岛素和谷歌分泌从胰岛监测。这将使能够确定 这些小分子在振荡性马酮释放中扮演的角色。在第三个目标中，脉搏马酮 轮廓将在监测葡萄糖输出的同时传递到肝细胞。这种方法将促进 了解动态马龙概况如何控制肝行为。拟议的研究是创新的 因为本提案中开发的微流体系统和测量方法将允许 胰岛和肝细胞行为的动力学首次观察。这些结果将提供 胰腺和肝脏之间相互作用的知识显着增加，这对于完全至关重要 了解葡萄糖稳态的机制及其在代谢疾病中的出现方式。最终， 这些知识有可能指导热发展，以减少与之相关的问题 II型糖尿病患者中不受管制的葡萄糖水平。