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Formal reasoning about systems biology using theorem proving

机译:使用定理证明关于系统生物学的形式推理

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摘要

System biology provides the basis to understand the behavioral properties of complex biological organisms at different levels of abstraction. Traditionally, analysing systems biology based models of various diseases have been carried out by paper-and-pencil based proofs and simulations. However, these methods cannot provide an accurate analysis, which is a serious drawback for the safety-critical domain of human medicine. In order to overcome these limitations, we propose a framework to formally analyze biological networks and pathways. In particular, we formalize the notion of reaction kinetics in higher-order logic and formally verify some of the commonly used reaction based models of biological networks using the HOL Light theorem prover. Furthermore, we have ported our earlier formalization of Zsyntax, i.e., a deductive language for reasoning about biological networks and pathways, from HOL4 to the HOL Light theorem prover to make it compatible with the above-mentioned formalization of reaction kinetics. To illustrate the usefulness of the proposed framework, we present the formal analysis of three case studies, i.e., the pathway leading to TP53 Phosphorylation, the pathway leading to the death of cancer stem cells and the tumor growth based on cancer stem cells, which is used for the prognosis and future drug designs to treat cancer patients.
机译:系统生物学为理解复杂生物在不同抽象级别的行为特性提供了基础。传统上,已经通过基于纸笔的证明和模拟来进行基于系统生物学的各种疾病模型的分析。然而,这些方法不能提供准确的分析,这对于人类医学的安全性至关重要的领域是一个严重的缺陷。为了克服这些限制,我们提出了一个框架来正式分析生物网络和途径。特别是,我们将反应动力学的概念形式化为高阶逻辑,并使用HOL Light定理证明器来正式验证一些常用的基于反应的生物网络模型。此外,我们已经将Zsyntax的早期形式化(即用于推理生物网络和途径的演绎语言)从HOL4移植到HOL Light定理证明者,以使其与上述反应动力学形式化兼容。为了说明所提出框架的有用性,我们对三个案例研究进行了形式分析,即导致TP53磷酸化的途径,导致癌症干细胞死亡的途径以及基于癌症干细胞的肿瘤生长的途径,这是用于治疗癌症患者的预后和未来药物设计。

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