Analysis and Extension of a Model for Oscillatory Islet Activity

振荡胰岛活动模型的分析和扩展

• 批准号: 1612193
• 负责人: Richard Bertram
• 金额: $ 29.42万
• 依托单位: Florida State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1612193&HistoricalAwards=false
• 关键词: Analysis; Extension; Model; Oscillatory; Islet

Type II diabetes makes up about 90% of all cases of diabetes world wide, and 368 million people were diagnosed with type II diabetes in 2013. Although it is a complex disease with many interacting factors, there is agreement that a major component is dysfunction of the pancreatic beta cells that release the hormone insulin. In normal individuals, these cells release insulin in pulses, with the pulse amplitude reflecting the glucose level. There is now conclusive evidence that pulsatile insulin is more effective than constant insulin at stimulating glucose-lowering actions of the liver. In addition, it has been shown that type II diabetics, and their nearest relatives, show disorganized insulin levels, rather than the more regular insulin pulses of non-diabetics. This project seeks to better understand the intracellular pathways that result in pulsatile insulin secretion from beta cells. It also seeks to understand how mice, which also exhibit pulsatile insulin secretion, compensate for genetic knockouts of key proteins in such a way that rhythmic cellular activity and insulin secretion is maintained. Overall, the project will yield insights into the complex biology of pulsatile insulin secretion, and will push forward mathematical analysis techniques that are useful in complex intracellular signaling systems such as those in pancreatic beta cells. Graduate students involved in this research project will receive broad interdisciplinary training in answering mathematical questions driven by experimental data. Publicly available software will also be produced. The Dual Oscillator Model has been under continuous development by Bertram and associates since it was first published in 2004. This model describes how three signaling pathways, metabolism, intracellular calcium dynamics, and electrical activity combine to produce pulsatile insulin secretion that is modulated by the extracellular glucose level. The complexity of the model makes it difficult to understand the dynamics of the system, but application of the fast/slow analysis technique allows one to take advantage of the separation of time scales of the model variables and formally decompose the system into subsystems that vary at different rates. This powerful multi-scale analysis technique will be applied to improve our understanding of oscillations in activity of the model beta cell that are induced by glucose and other substrates, as well as oscillations that are present in cells from mice in which different key proteins are genetically knocked out. Because there are several slowly changing variables, there are a number of different ways in which the fast/slow analysis technique can be used. These different approaches are explored, and will yield complementary insights. While the focus of the project is on oscillations in beta cell activity, the analysis approach used is applicable to a wide range of dynamic models, so the mathematical developments made in this project can be adapted to other complex biological systems.

II型糖尿病占全球所有糖尿病病例的90％，2013年有3.68亿人被诊断出患有II型糖尿病。尽管这是一种复杂的疾病，具有许多相互作用的因素，但人们认为，主要成分是胰腺β细胞的功能障碍，释放了激素胰岛素。在正常个体中，这些细胞在脉冲中释放胰岛素，脉冲幅度反映了葡萄糖水平。现在有确凿的证据表明，脉动胰岛素比持续的胰岛素在刺激肝脏的降糖作用方面更有效。此外，已经表明，II型糖尿病患者及其最近的亲属表现出混乱的胰岛素水平，而不是非糖尿病的更常规的胰岛素脉冲。该项目旨在更好地了解导致β细胞脉动胰岛素分泌的细胞内途径。它还试图了解如何表现出脉动胰岛素分泌的小鼠如何以节奏性细胞活性和胰岛素分泌的方式来补偿关键蛋白的遗传敲除。总体而言，该项目将对脉动胰岛素分泌的复杂生物学产生见解，并将推动在复杂细胞内信号系统（例如胰腺β细胞）中有用的数学分析技术。参与该研究项目的研究生将接受广泛的跨学科培训，以回答由实验数据驱动的数学问题。公开可用的软件也将生产。自2004年首次发布以来，双振荡器模型一直在贝特拉姆（Bertram）和同事（Associates）的连续发展中。该模型描述了三种信号通路，新陈代谢，细胞内钙动力学和电活动如何产生脉冲胰岛素分泌，从而受到细胞外糖外糖水平调节的脉冲胰岛素分泌。模型的复杂性使得很难理解系统的动力学，但是快速/慢分析技术的应用使人们可以利用模型变量的时间尺度的分离，并将系统正式分解为以不同速率变化的子系统。这种强大的多尺度分析技术将用于提高我们对由葡萄糖和其他底物诱导的模型β细胞活性的振荡的理解，以及来自小鼠细胞中存在的振荡，其中不同关键蛋白在遗传上被淘汰。因为有几种缓慢变化的变量，因此可以使用多种不同的方式来使用快速/慢分析技术。探索了这些不同的方法，并将产生互补的见解。尽管该项目的重点是β细胞活动中的振荡，但所使用的分析方法适用于广泛的动态模型，因此该项目中所做的数学发展可以适用于其他复杂的生物系统。