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

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health

Abstract

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