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Testing drugs with the help of mathematical modelling

借助数学模型测试药物

基本信息

批准号：
1804827
负责人：
金额：
--
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1804827
关键词：
Testing drugs help mathematical modelling

项目摘要

An important question that needs to be answered is: are there ways in which new drugs can be developed more time and cost efficiently while limiting the use of animals for testing? Before a new drug can be authorised for human usage, it needs to pass a series of screening tests. These take years to complete and by the time the final screening processes are reached, millions of pounds have already been spent in the development of the new drug. Often the early screening techniques which are used are far from realistic which is why many drugs pass these early tests, however most will fail in the final stages. This is a problem that must be solved as the pharmaceutical companies involved in the development of drugs are losing a lot of time and money, and animals are being used unnecessarily in the final stages of testing. In the early stages, testing usually consists of exposing cells or tissues to compounds in an in-vitro environment. Traditionally this involved a single layer of cells at the bottom of a petri dish filled with some fluid containing the compound. However, it is increasingly being recognised that more physiologically relevant in-vitro models are required [1]. There has therefore been a move to 2D and 3D systems which include multiple layers of cells; clusters of cells; cells contained within matrices and scaffolds and different combinations of these linked together using advanced cell culture apparatus. The inclusion of flow is becoming common in commercially available bioreactor systems [1,2]. Whilst these advances have provided enormous opportunity to fine-tune drug testing systems, to date this has not been achieved. An important question arises: what are the optimal experimental conditions which best mimic reality? Of course this will depend on the system at hand, however mathematical modelling can provide insights which can help to answer this important question. This project will mathematically model in-vitro drug testing systems. These models will be used to define an optimal set of experimental conditions that will give rise to the most clinically-relevant results.Objectivesi. Review the literature and identify a subset of systems where new mathematical modelling approaches are needed mostii. Develop mathematical models of fluid flow and nutrient/drug transport through 3D configurations of cells under controlled conditionsiii. Validate the models against experimental data from the literature and/or from interaction with collaboratorsiv. Develop mathematical models of the effect of the environment on the behaviour and health of the cells/tissuev. Use the mathematical models to provide guidance on the optimal experimental set-up for drug toxicity testing in the areas identified.MethodologyMathematical modelling can be used to identify the optimal conditions for testing drugs as it offers a framework which helps us understand how drugs and nutrients permeate through cells and clusters of cells (spheroids) [3]; the exposure and release of biomarkers; the effect of changes to the spatial arrangement and density of cells; the effect of flow and the exchange of nutrients and compounds within the media [1,2]. This will allow more realistic testing systems to be developed which will be more indicative of the outcome of the clinical in vivo tests.The models that will be developed in this project will be new and will be driven by the goal of developing systems which will identify drugs doomed to failure earlier. Regular conversations with relevant experimentalists and companies (e.g. Kirkstall Ltd) will be held to ensure the research remains relevant and well-informed. The models to be developed have the potential to lead to new design tools and to enable the rational design of new and more realistic drug testing systems.Alignment with EPSRC Strategies and Research AreasThis research sits broadly within the he

需要回答的一个重要问题是：有没有方法可以在限制使用动物进行试验的同时，开发出更多时间和成本更高的新药？在一种新药被授权用于人类之前，它需要通过一系列的筛选测试。这些工作需要数年时间才能完成，当最终筛选过程完成时，这种新药的开发已经花费了数百万英镑。通常情况下，使用的早期筛查技术远远不现实，这就是为什么许多药物通过了这些早期测试，然而大多数药物在最后阶段都会失败。这是一个必须解决的问题，因为参与药物开发的制药公司正在损失大量的时间和金钱，而且动物在试验的最后阶段被不必要地使用。在早期阶段，测试通常包括将细胞或组织暴露在体外环境中的化合物中。传统上，这需要在培养皿底部放置一层单层细胞，里面装满了含有化合物的液体。然而，越来越多的人认识到需要更多与生理相关的体外模型[1]。因此，已经转向2D和3D系统，该系统包括多层细胞、细胞簇、包含在基质和支架内的细胞以及使用先进的细胞培养设备连接在一起的这些细胞的不同组合。在商业上可用的生物反应器系统中，流的包含变得越来越普遍[1，2]。虽然这些进展为微调药物测试系统提供了巨大的机会，但到目前为止还没有实现这一点。一个重要的问题出现了：最能模拟现实的最佳实验条件是什么？当然，这将取决于手头的系统，但数学建模可以提供有助于回答这一重要问题的见解。该项目将对体外药物测试系统进行数学建模。这些模型将被用来定义一组最佳的实验条件，这些条件将产生与临床最相关的结果。回顾文献并确定需要新的数学建模方法的系统的子集。在可控条件下，通过细胞的三维构型建立流体流动和营养/药物运输的数学模型。根据文献中的实验数据和/或与合作者的交互验证模型。建立环境对细胞/组织的行为和健康影响的数学模型。使用数学模型来指导在确定的区域内进行药物毒性测试的最佳实验设置。方法数学模型可用于确定药物测试的最佳条件，因为它提供了一个框架，帮助我们了解药物和营养物质如何通过细胞和细胞团(球体)渗透[3]；生物标志物的暴露和释放；细胞空间排列和密度变化的影响；营养物质和化合物在介质中流动和交换的影响[1，2]。这将允许开发更现实的测试系统，它将更好地指示临床体内测试的结果。这个项目将开发的模型将是新的，并将受到开发系统的目标的驱动，该系统将识别注定要更早失败的药物。将定期与相关实验者和公司(例如Kirkstall Ltd.)进行对话，以确保研究保持相关性和消息灵通。将要开发的模型有可能导致新的设计工具，并使新的和更现实的药物测试系统的合理设计成为可能。与EPSRC战略和研究区域结盟这项研究广泛地位于HE