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Modelling the safety factor in neuromuscular transmission using 'population of models' approach

使用“模型群体”方法对神经肌肉传递的安全系数进行建模

基本信息

批准号：
1938567
负责人：
金额：
--
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1938567
关键词：
Modelling safety factor neuromuscular transmission

项目摘要

The project is concerned with computational modelling of the synaptic transmission at Drosophila NMJ, based on the data acquired via use of wide variety of techniques including electrophysiology, confocal microscopy and mutation studies. The data from these experiments will be utilised to calibrate a population of mechanistic stochastic models which will represent known variation in neurotransmission and be capable of predicting the behaviour of real life nerve-muscle system under various physiological and pathological conditions. This 'population of models' approach enables to model and observe the origins of variability within the process of neurotransmission, allowing to distinguish which molecular and genetic factors are involved in facilitation of neurotransmission. This will then allow to investigate the variability observed in Drosophila (and give insights into human) NMJ electrophysiology as well as possibly model and predict effects of various therapies (e.g. drug action) on various configurations of functional variables and constructing a basis for future experiments with personalised therapy in humans. The population models of Ca2+ and K+ channel interaction developed by computational analysis of data obtained from Drosophila will then be utilised to investigate proposed involvement of voltage-sensitive calcium channels in organophosphorus toxicity and the effects of various pesticide components and metabolites on permeability of ligand-gated ion channels to Ca2+ ions. These features are believed to lie at the root of Intermediate Myasthenic Syndrome, a condition which for unknown reason affects about 20% of patients exposed to high concentrations of pesticides and of whom ~ 50 % fail to recover. The population of models approach may help to explain this variability and allow

该项目涉及果蝇NMJ突触传递的计算建模，基于通过使用各种技术获得的数据，包括电生理学，共聚焦显微镜和突变研究。来自这些实验的数据将用于校准机械随机模型的群体，该模型将代表神经传递中的已知变化，并且能够预测各种生理和病理条件下的真实的生活神经-肌肉系统的行为。这种“模型群体”的方法能够模拟和观察神经传递过程中变异的起源，从而区分哪些分子和遗传因素参与了神经传递的促进。然后，这将允许调查在果蝇中观察到的变异性（并提供对人类的见解）NMJ电生理学以及可能的模型和预测各种治疗（例如药物作用）对功能变量的各种配置的影响，并为未来在人类中进行个性化治疗的实验构建基础。人口模型的Ca 2+和K+通道的相互作用，从果蝇获得的数据的计算分析，然后将被用来调查建议参与的电压敏感性钙通道的有机磷毒性和各种农药成分和代谢产物对配体门控离子通道的渗透性的影响，以Ca 2+离子。这些特征被认为是中间型肌无力综合征的根源，这种病症由于未知原因影响了约20%暴露于高浓度农药的患者，其中约50%未能恢复。模型群体方法可能有助于解释这种变异性，