RESUMO
Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development.
Assuntos
Hepatócitos/fisiologia , Inativação Metabólica/fisiologia , Fígado/fisiologia , Modelos Biológicos , Acetaminofen/farmacocinética , Alopurinol/administração & dosagem , Amônia/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Biologia Computacional/métodos , Simulação por Computador , Hepatócitos/metabolismo , Humanos , Hiperuricemia/metabolismo , Hiperuricemia/terapia , Fígado/citologia , Metabolismo/fisiologia , Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia , Ácido Úrico/metabolismoRESUMO
BACKGROUND: Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor κB (NF-κB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner. RESULTS: This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-κB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability. CONCLUSIONS: Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-κB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity.
Assuntos
Apoptose/fisiologia , Modelos Biológicos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Caspase 3/farmacologia , Caspase 8/metabolismo , Linhagem Celular , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Modelos Lineares , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Bone is a dynamic living tissue that undergoes continuous adaptation of its mass and structure in response to mechanical and biological environment demands. Studies of bone adaptation have focused on metabolic or mechanical stimulus, but mathematical models of bone adaptation considering both, are not available by now. In this paper, we propose a mathematical model of bone adaptation during a remodeling cycle due to mechanical stimulus with the introduction of osteocytes as mechanotransducers. The model captures qualitatively very well the bone adaptation and cell interactions during the bone remodeling.