Relevance of systems pharmacology in drug discovery

The pharmaceutical industry is in the process of re-inventing its pipeline in an attempt to overcome its increasing phase II and III attrition rates. Here, we describe how systems pharmacology can be used as a risk assessment tool to alleviate this problem before bringing in larger investments. We propose that this translational research tool could provide a valuable, complementary addition to other emerging innovative approaches for target identification and validation in discovery and, ultimately, for aiding clinical trial optimization

ASPASIA: A toolkit for evaluating the effects of biological interventions on SBML model behaviour

A calibrated computational model reflects behaviours that are expected or observed in a complex system, providing a baseline upon which sensitivity analysis techniques can be used to analyse pathways that may impact model responses. However, calibration of a model where a behaviour depends on an intervention introduced after a defined time point is difficult, as model responses may be dependent on the conditions at the time the intervention is applied. We present ASPASIA (Automated Simulation Parameter Alteration and SensItivity Analysis), a cross-platform, open-source Java toolkit that addresses a key deficiency in software tools for understanding the impact an intervention has on system behaviour for models specified in Systems Biology Markup Language (SBML). ASPASIA can generate and modify models using SBML solver output as an initial parameter set, allowing interventions to be applied once a steady state has been reached. Additionally, multiple SBML models can be generated where a subset of parameter values are perturbed using local and global sensitivity analysis techniques, revealing the model's sensitivity to the intervention. To illustrate the capabilities of ASPASIA, we demonstrate how this tool has generated novel hypotheses regarding the mechanisms by which Th17-cell plasticity may be controlled in vivo. By using ASPASIA in conjunction with an SBML model of Th17-cell polarisation, we predict that promotion of the Th1-associated transcription factor T-bet, rather than inhibition of the Th17-associated transcription factor RORγt, is sufficient to drive switching of Th17 cells towards an IFN-γ-producing phenotype. Our approach can be applied to all SBML-encoded models to predict the effect that intervention strategies have on system behaviour. ASPASIA, released under the Artistic License (2.0), can be downloaded from http://www.york.ac.uk/ycil/software

Transcriptomic and genetic studies identify NFAT5 as a candidate gene for cocaine dependence

Contains fulltext : 152880.pdf (publisher's version ) (Open Access)Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study, we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y-differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed after a 5 muM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 muM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (SNPs) in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3'-untranslated region of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence