Theory of Electrical Activity and Insulin Release for the Pancreatic Beta-Cell

本项目的长期目标是了解 控制胰岛素分泌的分子机制 胰腺B细胞 这些机制是复杂的， 理论方法，包括动力学分子理论， 非平衡热力学，将被用来制定 适当的数学描述。 我们的方法是基于 胰岛素分子过程的实验方案 颗粒形成、Ca 2+处理、磷酸化和胰岛素 颗粒胞吐作用 将这些方案转化为 过程，然后进入速率方程，我们将探索 以下机制对胰岛素释放速率的影响： 1)质膜的复杂电活动与 2）胰岛B细胞间的电耦合; 3)Ca 2+处理机制; 4）基于磷脂的生化 参与胰岛素分泌控制的机制。 这些 将使用数学分析和 计算机模拟相应的常微分 方程 关于比率的充分实验信息 的过程是可以证明这些计算， 将与正在进行的实验工作密切配合。 的 这项工作将提供深入了解细胞分子机制 II型糖尿病（非胰岛素依赖型）。 更 一般来说，这项工作将有助于提供一个理论基础， 细胞生物学和细胞生理学。 细胞的复杂性 需要良好的分析基础来补充实验 研究，以发展良好的理论基础， 了解细胞功能的机制。

The long-term objective of this project is to understand the molecular mechanisms that control secretion of insulin from the pancreatic B-cell. These mechanisms are complex, and quantitative theoretical methods, including the kinetic-molecular theory of nonequilibrium thermodynamics, will be used to formulate the appropriate mathematical description. Our approach is based on experimental schemes of molecular processes involved in insulin granule formation, Ca2+ handling, phosphorylation, and insulin granule exocytosis. Translating these schemes into elementary processes, and thence into rate equations, we will explore the effect of the following mechanisms on rate of insulin release: 1) Complex electrical activity of the plasma membrane related to Ca2+ and pH; 2) electrical coupling between B-cells in islets; 3) Ca2+ handling mechanisms; 4) phospholipid-based biochemical mechanisms involved in the control of insulin secretion. These mechanisms will be explored using mathematical analysis and computer simulations of the corresponding ordinary differential equations. Sufficient experimental information regarding the rates of the processes is available to justify these calculations, which will be interfaced closely with ongoing experimental work. The work will provide insight into the cellular-molecular mechanisms involved in type II (noninsulin dependent) diabetes. More generally, this work will help provide a basis for a theoretical cell biology and cell physiology. The complexity of the cell requires a good analytical foundation to complement experimental studies in order to develop a good theoretical basis for understanding the mechanism of cellular function.