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 我们先前已经描述了P2X7受体的Stojilkovic实验实验室（NICHD）合作开发的动力学模型。 该受体是由细胞外ATP激活的配体门控离子通道，并在垂体细胞和巨噬细胞中被普遍表达。 在低浓度的ATP下，该配体门控钙通道的作用与P2X家族的其他成员一样，但延长或反复暴露于高ATP浓度会导致其扩张并大量大量钙涌入。 这种不寻常且复杂的行为导致提出正常和超正常电流是由于两个不同的通道引起的，但是该模型是具有8个状态的马尔可夫州模型，表明一个通道可以扮演两个角色。 当钙很小时，P2X7既可以充当传统的钙通道，又可以作为细胞生长和分化模式之间的切换，当钙涌入钙很大时。 这可能是免疫系统如何在适当反应和反应过度反应之间保持平衡的重要组成部分。 已经提出了P2X7受体中的多态性作为NOD小鼠的易感基因，该基因是1型糖尿病的模型。 我们以前已经对P2X2受体以及P2X7进行了建模（参见参考文献＃1，2012报告）。 面对维持的ATP时，通过该受体的电流迅速关闭，但是模型和实验表明，受体仍然扩张，因为它具有在用ATP刺激后进行大型有机阳离子的能力。 该模型表明，扩张被脱敏掩盖。 在当前的报告期间，我们返回到P2X7受体并添加了脱敏，该功能已知存在，但在第一次迭代中被忽略了，以便将重点放在扩张和记忆的关键特征上。 两个受体的模型在结构上非常相似，但在过渡速率上进行数量差异。 现在，更新的P2X7模型同时表现出扩张和脱敏，但与P2X2相反，扩张占主导地位。 两种模型之间的相似性支持我们的整体假设，即P2X受体具有共同的特征核心，但定量差异以实现不同的最终行为。 我们计划通过将模型扩展到P2X家族的其他成员来进一步检验这一假设。