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.

朗格汉斯个体胰岛胰岛素和胰高血糖素的分泌动态及其作用 这些动态在肝脏葡萄糖调节中的作用尚不清楚。罗珀的长期目标 实验室的目的是解码细胞通讯，以了解正常的生物功能和 疾病进展。该提案的目的是确定调节动态的控制机制 胰岛的激素释放以及肝脏的动态激素输入如何优化净肝葡萄糖控制 由肝脏。核心假设是，朗格汉斯岛释放的胰岛素和胰高血糖素与 肝脏产生一个反馈回路，同步胰岛行为，设定胰岛素的阶段， 胰高血糖素振荡，并促进最佳的肝脏代谢。执行这项工作的理由是 彻底了解葡萄糖调节激素分泌和葡萄糖处理的动态 肝脏可能会导致治疗方法的设计，以减轻与肝脏相关的并发症 糖尿病和其他代谢性疾病。在强有力的初步数据的指导下，这一假设将得到检验 追求三个具体目标：1) 确定胰岛释放葡萄糖调节激素的动态，2) 确定影响荷尔蒙反应的胰岛小分子分泌的动态，以及 3) 确定 肝细胞对动态激素谱的代谢反应。在第一个目标下，采用一种新颖的方法 将利用高时间分辨率测量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测定相结合，以实现激素振荡幅度、频率和 待识别的相位关系。在第二个目标中，γ-氨基丁酸和谷氨酸的分泌将被 与胰岛素和胰高血糖素分泌同时监测胰岛。这将能够确定 这些小分子在振荡激素释放中发挥的作用。第三个目标，脉动激素 配置文件将被传送到肝细胞，同时监测葡萄糖输出。该方法将有利于 了解动态激素分布如何控制肝脏行为。所提出的研究具有创新性 因为本提案中开发的微流体系统和测量方法将允许 首次观察到胰岛和肝细胞行为的动态。这些结果将提供 对胰腺和肝脏之间相互作用的了解显着增加，这对于充分了解胰腺和肝脏之间的相互作用至关重要 了解葡萄糖稳态的机制及其在代谢疾病中如何出错。最终， 这些知识有可能指导治疗方法的开发，以减少与疾病相关的问题 II 型糖尿病患者的血糖水平不受调节。