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A control theoretic three timescale model for analyzing energy management in mammalian cancer cells.

ABSTRACT: 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 ? (HIF-1 ? ) 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).

SUBMITTER: Dasgupta A

PROVIDER: S-EPMC7809419 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A control theoretic three timescale model for analyzing energy management in mammalian cancer cells.

Dasgupta Abhijit A Bakshi Abhisek A Chowdhury Nirmalya N De Rajat K RK

Computational and structural biotechnology journal 20201229

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 ...[more]

PMID: 33510857

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Project description:Previous studies have used the zebrafish to investigate the biology of lens crystallin proteins and their roles in development and disease. However, little is known about zebrafish ?-crystallin promoter function, how it compares to that of mammals, or whether mammalian ?-crystallin promoter activity can be assessed using zebrafish embryos. We injected a variety of ?-crystallin promoter fragments from each species combined with the coding sequence for green fluorescent protein (GFP) into zebrafish zygotes to determine the resulting spatiotemporal expression patterns in the developing embryo. We also measured mRNA levels and protein abundance for all three zebrafish ?-crystallins. Our data showed that mouse and zebrafish ?A-crystallin promoters generated similar GFP expression in the lens, but with earlier onset when using mouse promoters. Expression was also found in notochord and skeletal muscle in a smaller percentage of embryos. Mouse ?B-crystallin promoter fragments drove GFP expression primarily in zebrafish skeletal muscle, with less common expression in notochord, lens, heart and in extraocular regions of the eye. A short fragment containing only a lens-specific enhancer region increased lens and notochord GFP expression while decreasing muscle expression, suggesting that the influence of mouse promoter control regions carries over into zebrafish embryos. The two paralogous zebrafish ?B-crystallin promoters produced subtly different expression profiles, with the aBa promoter driving expression equally in notochord and skeletal muscle while the ?Bb promoter resulted primarily in skeletal muscle expression. Messenger RNA for zebrafish ?A increased between 1 and 2 days post fertilization (dpf), ?Ba increased between 4 and 5 dpf, but ?Bb remained at baseline levels through 5 dpf. Parallel reaction monitoring (PRM) mass spectrometry was used to detect ?A, aBa, and ?Bb peptides in digests of zebrafish embryos. In whole embryos, ?A-crystallin was first detected by 2 dpf, peaked in abundance by 4-5 dpf, and was localized to the eye. ?Ba was detected in whole embryo at nearly constant levels from 1-6 dpf, was also localized primarily to the eye, and its abundance in extraocular tissues decreased from 4-7 dpf. In contrast, due to its low abundance, no ?Bb protein could be detected in whole embryo, or dissected eye and extraocular tissues. Our results show that mammalian ?-crystallin promoters can be efficiently screened in zebrafish embryos and that their controlling regions are well conserved. An ontogenetic shift in zebrafish aBa-crystallin promoter activity provides an interesting system for examining the evolution and control of tissue specificity. Future studies that combine these promoter based approaches with the expanding ability to engineer the zebrafish genome via techniques such as CRISPR/Cas9 will allow the manipulation of protein expression to test hypotheses about lens crystallin function and its relation to lens biology and disease.

Dataset Information

A control theoretic three timescale model for analyzing energy management in mammalian cancer cells.

Publications

A control theoretic three timescale model for analyzing energy management in mammalian cancer cells.

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