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，将使用定量的理论方法，包括非平衡热力学的动力学-分子理论，来制定适当的数学描述。我们的方法是基于涉及胰岛素颗粒形成、钙处理、磷酸化和胰岛素颗粒胞吐的分子过程的实验方案。将这些过程转化为基本过程，并由此转化为速率方程，我们将探讨以下机制对胰岛素释放速率的影响：1)与钙和pH有关的质膜复杂的电活动；2)胰岛B细胞之间的电耦合；3)钙的处理机制；4)参与控制胰岛素分泌的磷脂生化机制。这些机制将通过数学分析和相应常微分方程式的计算机模拟来探索。关于过程速率的足够实验信息可以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相关。这项工作将为深入了解II型(非胰岛素依赖型)糖尿病的细胞-分子机制提供依据。更广泛地说，这项工作将有助于为细胞生物学和细胞生理学提供理论基础。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的机制发展良好的理论基础。

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.