期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2021
卷号：19
页码：477-508
DOI：10.1016/j.csbj.2020.12.019
出版社：Computational and Structural Biotechnology Journal
摘要：Interaction among different pathways, such as metabolic, signaling and gene regulatory networks, of cellular system is responsible to maintain homeostasis in a mammalian cell. Malfunctioning of this cooperation may lead to many complex diseases, such as cancer and type 2 diabetes. Timescale differences among these pathways make their integration a daunting task. Metabolic, signaling and gene regulatory networks have three different timescales, such as, ultrafast, fast and slow respectively. The article deals with this problem by developing a support vector regression (SVR) based three timescale model with the application of genetic algorithm based nonlinear controller. The proposed model can successfully capture the nonlinear transient dynamics and regulations of such integrated biochemical pathway under consideration. Besides, the model is quite capable of predicting the effects of certain drug targets for many types of complex diseases. Here, energy and cell proliferation management of mammalian cancer cells have been explored and analyzed with the help of the proposed novel approach. Previous investigations including in silico / in vivo / in vitro experiments have validated the results (the regulations of glucose transporter 1 (glut1), hexokinase (HK), and hypoxia-inducible factor-1 α (HIF-1 α ) among others, and the switching of pyruvate kinase (M2 isoform) between dimer and tetramer) generated by this model proving its effectiveness. Subsequently, the model predicts the effects of six selected drug targets, such as, the deactivation of transketolase and glucose-6-phosphate isomerase among others, in the case of mammalian malignant cells in terms of growth, proliferation, fermentation, and energy supply in the form of adenosine triphosphate (ATP).
关键词：Pathway integration ; Timescale ; MIMO ; Support vector regression ; Genetic algorithm ; Warburg effect
