'Multilevel modelling of neuronal function: combining metabotropic pathways and membrane excitability in silico for the quick screening of drugs'

神经元起着信息传递的作用。它们在亚细胞尺度上整合来自环境的信息，产生适当的电生理反应。霍奇金和赫胥利将实验记录与等效电路的数学建模相结合，阐明了在质膜水平上发生的电过程的理解。然而，描述细胞信号传导对细胞反应影响的定量模型是缺乏的。腺苷是一种结合A1 （Gi）和A2 （Gs）受体的神经递质。A1和A2刺激通过K+渗透性改变导致神经元兴奋性改变。在这个项目中，我们的目标是将腺苷受体信号转导的数学模型（Tindall）与神经元的霍奇金-赫胥利模型（Tsaneva-Atanasova）结合起来，生成一个硅统一模型，预测暴露于化学刺激后的神经元功能。我们将用全神经元膜片钳记录（Tamagnini）来测试模型的预测能力。在项目期间制定的数学模型将利用微分方程（常方程和偏方程）的理论进行数值和解析（例如动力系统理论，渐近方法）的求解和分析。成功的候选人将参与湿实验室实验的设计和实施，以测试和提供数学模型。候选人将接受全细胞膜片钳技术的培训，并通过执行动态钳来测试模型在活体系统上的有效性。统一模型的设计和验证旨在为临床前，伦理，高通量筛选新开发的具有生物活性的分子及其对神经元功能的作用提供工具（软件）。

Neurons work as information relays. They integrate information received from the environment at the subcellular scale, generating an appropriate electrophysiological response. The understanding of electrical processes happening at the plasma membrane level has been clarified by Hodgkin and Huxley, combining experimental recordings with mathematical modelling of equivalent electrical circuits. However, quantitative models describing the effects of cell signalling on the cellular response are lacking.Adenosine is a neurotransmitter binding both A1 (Gi) and A2 (Gs) receptors. A1 and A2 stimulation results in altered neuronal excitability via K+ permeability changes. In this project, we aim to combine a mathematical model of adenosine receptor signal transduction (Tindall) with the Hodgkin-Huxley model of a neuron (Tsaneva-Atanasova), to generate an in-silico unified model, predictive of neuronal function following exposure to chemical stimulation. We will test the predictive capability of the model with whole-neuron patch-clamp recordings (Tamagnini).The mathematical models formulated during the project will utilise the theory of differential equations (ordinary and partial) solved and analysed both numerically and analytically (e.g. dynamical systems theory, asymptotic methods). The successful candidate will be involved in the design and undertaking of wet laboratory experiments for testing and informing the mathematical models. The candidate will be trained in whole cell patch clamp techniques, with the value added of performing dynamic clamp to test the validity of the model on to a live system. The design and validation of the unified model is aimed at providing a tool (software) for the pre-clinical, ethical, high-throughput screening of newly developed molecules with biological activity and their action on neuronal function.