Mathematical Modeling of Neurons and Endocrine Cells

神经元和内分泌细胞的数学模型

• 批准号: 8741340
• 负责人: Arthur Sherman
• 金额: $ 6.23万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741340
• 关键词: Action Potentials; Apoptosis; Area; Behavior; Beta Cell; Calcium; Calcium Channel; Cations; Cell Differentiation process; Cells; Chemicals; Collaborations; Complex; Coupled; Endocrine; Endoplasmic Reticulum; Equation; Equilibrium; Exhibits; Exocytosis; Exposure to; Family; Gated Ion Channel; Genetic Polymorphism; Hodgkin Disease; Hypothalamic structure; Immune System Part; Inbred NOD Mice; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Kinetics; Ligands; Masks; Mediating; Mediator of activation protein; Membrane; Memory; Modeling; National Institute of Child Health and Human Development; Nerve; Neurons; Nobel Prize; Organelles; P2X-receptor; Pituitary Gland; Play; Purinoceptor; Reporting; Role; Second Messenger Systems; Signaling Protein; Specificity; Susceptibility Gene; System; Testing; Update; Work; base; cell growth; cell type; desensitization; extracellular; interest; macrophage; mathematical model; member; neglect; receptor; research study; salivary acinar cell; second messenger; tool

Purinergic Receptors We have previously described (see 2010 and 2012 reports) a kinetic model, developed in collaboration with the Stojilkovic experimental lab (NICHD), of the P2X7 receptor. This receptor is a ligand-gated ion channel activated by extracellular ATP and is expressed ubiquitously, including in pituitary cells and macrophages. At low concentrations of ATP, this ligand-gated calcium channel acts much like other members of the P2X family, but prolonged or repeated exposure to high ATP concentrations causes it to dilate and gate a massive influx of calcium. This unusual and complex behavior had led to proposals that the normal and super-normal currents are due to two different channels, but the model, a Markov state model with 8 states, showed that a single channel could play both roles. P2X7 can act both as a conventional calcium channel and as switch between a mode of cell growth and differentiation, when calcium is small, and a mode of programmed cell death, when calcium influx is large. This could be an important part of how the immune system maintains a balance between responding appropriately and over-reacting to inflammation. A polymorphism in the P2X7 receptor has been proposed as a susceptibility gene for the NOD mouse, a model for type 1 diabetes. We have previously modeled P2X2 receptors as well as P2X7 (See Ref. # 1, 2012 report). The current through this receptor rapidly shuts off in the face of maintained ATP but the model and experiments showed that the receptor nonetheless dilates, because it gains the ability to conduct large organic cations after stimulation with ATP. The model showed that the dilation was masked by desensitization. In the current report period, we returned to the P2X7 receptor and added desensitization, a feature that was known to be present but was neglected in the first iteration in order to keep the focus on the key features of dilation and memory. The models of the two receptors are structurally very similar but differ quantitatively in the transition rates. The updated P2X7 model now exhibits both dilation and desensitization, but, in contrast to P2X2, dilation dominates. The similarity between the two models lends support to our overall hypothesis that P2X receptors have a common core of features but differ quantitatively to achieve different end behaviors. We plan to test this hypothesis further by extending the model to other members of the P2X family.

嘌呤能受体 我们之前描述过（参见 2010 年和 2012 年的报告）与 Stojilkovic 实验实验室 (NICHD) 合作开发的 P2X7 受体动力学模型。 该受体是一种由细胞外 ATP 激活的配体门控离子通道，广泛表达，包括在垂体细胞和巨噬细胞中。 在低浓度 ATP 下，这种配体门控钙通道的作用与 P2X 家族的其他成员非常相似，但长期或反复暴露于高 ATP 浓度会导致其扩张并门控钙的大量流入。 这种不寻常且复杂的行为导致有人提出正常电流和超正常电流是由两个不同的通道引起的，但该模型（具有 8 个状态的马尔可夫状态模型）表明，单个通道可以发挥这两种作用。 P2X7 既可以充当传统的钙通道，也可以充当细胞生长和分化模式（当钙量较少时）和程序性细胞死亡模式（当钙流入量较大时）之间的转换。 这可能是免疫系统如何在对炎症的适当反应和过度反应之间保持平衡的重要部分。 P2X7 受体的多态性已被提议作为 NOD 小鼠（1 型糖尿病模型）的易感基因。 我们之前已经对 P2X2 受体和 P2X7 受体进行了建模（参见参考文献#1，2012 年报告）。 面对维持的 ATP，通过该受体的电流会迅速关闭，但模型和实验表明该受体仍然会扩张，因为它在 ATP 刺激后获得了传导大有机阳离子的能力。 该模型显示扩张被脱敏所掩盖。 在当前报告期内，我们回到了 P2X7 受体并添加了脱敏功能，这是已知存在但在第一次迭代中被忽略的功能，以便将注意力集中在扩张和记忆的关键功能上。 两种受体的模型在结构上非常相似，但在转换速率上存在定量差异。 更新后的 P2X7 模型现在同时表现出扩张和脱敏，但与 P2X2 相比，扩张占主导地位。 两个模型之间的相似性支持了我们的总体假设，即 P2X 受体具有共同的核心特征，但在数量上有所不同，以实现不同的最终行为。 我们计划通过将该模型扩展到 P2X 家族的其他成员来进一步检验这一假设。