Systems biology for organotypic cell cultures

Grego, Sonia; Dougherty, Edward R.; Alexander, Francis J.; Auerbach, Scott S.; Berridge, Brian R.; Bittner, Michael; Casey, Warren; Cooley, Phillip; Dash, Ajit; Ferguson, Stephen S. G.; Fennell, Timothy R.; Hawkins, Brian T.; Hickey, Anthony; Kleensang, André; Liebman, Michael; Martin, Florian; Maull, Elizabeth A.; Paragas, Jason; Qiao, Guilin Gary; Ramaiahgari, Sreenivasa; Sumner, Susan; Yoon, Miyoung

doi:10.14573/altex.1608221

Cited by 11 publications

(3 citation statements)

References 54 publications

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“…Another characteristic of in vitro cellbased biological systems is their adaptability to any therapeutic treatment that might induce drug resistance. We also need to verify whether organotypic cultures manifest the emergent properties of disease/toxicity (Grego et al, 2017). These and other challenges may lead to failure for validation of even the most powerful predictive molecular network.…”

Section: Cell-based Approachesmentioning

confidence: 99%

Molecular networks in Network Medicine: Development and applications

Silverman

Schmidt

Anastasiadou

et al. 2020

WIREs Mechanisms of Disease

156

118

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Network Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein-protein interaction networks, correlation-based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in identifying key genes within genetic association regions, and limited applications to human diseases.

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Section: Cell-based Approachesmentioning

confidence: 99%

Molecular networks in Network Medicine: Development and applications

Silverman

Schmidt

Anastasiadou

et al. 2020

WIREs Mechanisms of Disease

156

118

View full text Add to dashboard Cite

show abstract

“…Spatialised simulations have been successfully applied to the design and optimisation of cancer-targeting nanoparticles, and similar methodologies could be applied to the neutralisation of venom toxins (Hauert et al, 2013;Stillman et al, 2021Stillman et al, , 2020. Spatial models could be validated in vitro using organotypic tissue models, which have recently been applied to snakebite envenomation (Ahmadi et al, 2022;Grego et al, 2017). This could help reduce reliance on animal testing within antivenom research, and contribute to the preclinical testing of novel antivenom formulations.…”

Section: Future Work and Applications Of Pharmacokinetic Modelling In...mentioning

confidence: 99%

Global parameter optimisation and sensitivity analysis of antivenom pharmacokinetics and pharmacodynamics

Morris

Blee

Hauert

2023

Preprint

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In recent years it has become possible to design snakebite antivenoms with diverse pharmacokinetic properties. Owing to the pharmacokinetic variability of venoms, the choice of antivenom scaffold may influence a treatments neutralisation coverage. Computation offers a useful medium through which to assess the pharmacokinetics and pharmacodynamics of envenomation-treatment systems, as antivenoms with identical neutralising capacities can be simulated. In this study, we simulate envenomation and treatment with a variety of antivenoms, to define the properties of effective antivenoms. Systemic envenomation and treatment were described using a two-compartment pharmacokinetic model. Treatment of Naja sumatrana and Cryptelytrops purpureomaculatus envenomation was simulated with a set of 200,000 theoretical antivenoms across 10 treatment time delays. These two venoms are well-characterised and have differing pharmacokinetic properties. The theoretical antivenom set varied across molecular weight, dose, kon, koff, and valency. The best and worst treatments were identified using an area under the curve metric, and a global sensitivity analysis was performed to quantify the influence of the input parameters on treatment outcome. The simulations show that scaffolds of diverse molecular formats can be effective. Molecular weight and valency have a negligible direct impact on treatment outcome, however low molecular weight scaffolds offer more flexibility across the other design parameters, particularly when treatment is delayed. The simulations show kon to primarily mediate treatment efficacy, with rates above 10*5 M-1s-1 required for the most effective treatments. koff has the greatest impact on the performance of less effective scaffolds. While the same scaffold preferences for improved treatment are seen for both model snakes, the parameter bounds for C. purpureomaculatus envenomation are more constrained. This paper establishes a computational framework for the optimisation of antivenom design.

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“…The circulation of the cell culture medium can further assist in modeling multi-organ interactions with paracrine and endocrine signaling. OCCs in combination with advanced cellular assays, such as high-content analyses and the omics approach, provide more in-depth insights into biology in a quantitative and multi-parametric manner than animal experiments 19 . OOCs have been used to recapitulate GLA in vitro and to demonstrate the role of crosstalk via the GLA in pathological situations, including fatty liver disease 20,21 and inflammation 22 , for in vitro pharmacokinetic studies 23 .…”

mentioning

confidence: 99%

Integrated-gut-liver-on-a-chip platform as an in vitro human model of non-alcoholic fatty liver disease

et al. 2023

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Non-alcoholic fatty liver disease (NAFLD) afflicts a significant percentage of the population; however, no effective treatments have yet been established because of the unsuitability of in vitro assays and animal experimental models. Here, we present an integrated-gut-liver-on-a-chip (iGLC) platform as an in vitro human model of the gut-liver axis (GLA) by co-culturing human gut and liver cell lines interconnected via microfluidics in a closed circulation loop, for the initiation and progression of NAFLD by treatment with free fatty acids (FFAs) for 1 and 7 days, respectively. Co-cultured Caco-2 gut-mimicking cells and HepG2 hepatocyte-like cells demonstrate the protective effects from apoptosis against FFAs treatment, whereas mono-cultured cells exhibit induced apoptosis. Phenotype and gene expression analyses reveal that the FFAs-treated gut and liver cells accumulated intracellular lipid droplets and show an increase in gene expression associated with a cellular response to copper ions and endoplasmic reticulum stress. As an in vitro human GLA model, the iGLC platform may serve as an alternative to animal experiments for investigating the mechanisms of NAFLD.

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Systems biology for organotypic cell cultures

Cited by 11 publications

References 54 publications

Molecular networks in Network Medicine: Development and applications

Molecular networks in Network Medicine: Development and applications

Global parameter optimisation and sensitivity analysis of antivenom pharmacokinetics and pharmacodynamics

Integrated-gut-liver-on-a-chip platform as an in vitro human model of non-alcoholic fatty liver disease

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