Multiscale Modeling & Analysis of Circadian Rhythm

多尺度建模

• 批准号: 7161838
• 负责人: Linda R. Petzold
• 金额: $ 33.15万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-11 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161838
• 关键词: Rodentias; biological clocks; calcium flux; cell cell interaction; cell population study; circadian rhythms; computational neuroscience; enzyme activity; mathematical model; membrane potentials; model design /development; neural information processing; neurogenetics; neuropeptide receptor; suprachiasmatic nucleus; tissue /cell culture; vasoactive intestinal peptide

DESCRIPTION (provided by applicant): A multicellular model of mammalian circadian rhythm generation and synchronization will be developed through an integrated program ofneurophysiological experiments, theoretical modeling and multi-scale systems analysis and computation. Our hypothesis is that the coupling of individual pacemaker neurons is mediated by the neurotransmitter vasoactive intestinal peptide (VIP) prevalent in the suprachiasmatic nucleus (SCN). Experiments will identify the dose- and phase-dependence of SCN neurons on VIP for circadian synchrony. These experiments will guide the development of a pacemaker cell model in which a detailed description of the gene regulatory network responsible for rhythmic electrical activity is combined with a simplified description of the VIP signaling pathways implicated in circadian coupling. The pacemaker model will be used as a building block in the construction of neural population models that account for the known anatomy and physiology of the SCN including the core and shell divisions and the distribution of VIP producing cells in the two divisions. The resulting models will cover a wide range of time and length scales ranging from the gene regulation level to the neuron signaling level to the tissue level. Deterministic simulation codes will be developed to allow the efficient simulation of large ensembles of coupled SCN neurons. Stochastic effects at the gene and signaling levels will be studied by developing combined deterministic/stochastic simulation codes. Parallel theoretical work on the population model and a simplified surrogate model will yield insights into stochastic effects in large neuron populations. The combined experimental, theoretical and computational work will allow systematic perturbation analysis of the roles of individual neurons and their interconnections on the precision and robustness of circadian rhythm generation.

描述（由申请人提供）：将通过神经生理学实验、理论建模以及多尺度系统分析和计算的综合程序开发哺乳动物昼夜节律生成和同步的多细胞模型。我们的假设是，个体起搏神经元的耦合是由视交叉上核（SCN）中普遍存在的神经递质血管活性肠肽（VIP）介导的。实验将确定 SCN 神经元对 VIP 的剂量和相位依赖性，以实现昼夜节律同步。这些实验将指导起搏器细胞模型的开发，其中负责节律性电活动的基因调控网络的详细描述与昼夜节律耦合涉及的 VIP 信号通路的简化描述相结合。起搏器模型将用作构建神经群体模型的构建块，该模型解释了 SCN 的已知解剖学和生理学，包括核心和外壳分裂以及两个分裂中 VIP 产生细胞的分布。由此产生的模型将涵盖从基因调控水平到神经元信号传导水平再到组织水平的广泛时间和长度尺度。将开发确定性模拟代码，以允许对耦合 SCN 神经元的大型集合进行有效模拟。将通过开发组合的确定性/随机模拟代码来研究基因和信号水平的随机效应。对群体模型和简化代理模型的并行理论工作将深入了解大型神经元群体中的随机效应。实验、理论和计算相结合的工作将允许对单个神经元的作用及其互连对昼夜节律生成的精度和鲁棒性的影响进行系统的扰动分析。