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

该项目的长期目标是了解控制胰腺b细胞分泌胰岛素的分子机制。这些机制是复杂的，定量的理论方法，包括非平衡热力学的动力学分子理论，将被用来制定适当的数学描述。我们的方法是基于参与胰岛素颗粒形成、Ca2+处理、磷酸化和胰岛素颗粒胞吐的分子过程的实验方案。将这些方案转化为基本过程，进而转化为速率方程，我们将探索以下机制对胰岛素释放速率的影响：1)与Ca2+和pH相关的质膜复杂电活动；2)胰岛内b细胞间的电偶联；3) Ca2+处理机制；4)参与胰岛素分泌控制的基于磷脂的生化机制。这些机制将探索使用数学分析和计算机模拟相应的常微分方程。关于这些过程的速率有足够的实验信息来证明这些计算是合理的，这些计算将与正在进行的实验工作密切结合。这项工作将为II型（非胰岛素依赖型）糖尿病的细胞分子机制提供见解。更一般地说，这项工作将有助于为理论细胞生物学和细胞生理学提供基础。细胞的复杂性需要良好的分析基础来补充实验研究，以便为理解细胞功能机制建立良好的理论基础。

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.