A computational model of lipopolysaccharide-induced nuclear factor kappa B activation: a key signalling pathway in infection-induced preterm labour.
Preterm birth is the single biggest cause of significant neonatal morbidity and mortality, and the incidence is rising. Development of new therapies to treat and prevent preterm labour is seriously hampered by incomplete understanding of the molecular mechanisms that initiate labour at term and preterm. Computational modelling provides a new opportunity to improve this understanding. It is a useful tool in (i) identifying gaps in knowledge and informing future research, and (ii) providing the basis for an in silico model of parturition in which novel drugs to prevent or treat preterm labour can be "tested". Despite their merits, computational models are rarely used to study the molecular events initiating labour. Here, we present the first attempt to generate a dynamic kinetic model that has relevance to the molecular mechanisms of preterm labour. Using published data, we model an important candidate signalling pathway in infection-induced preterm labour: that of lipopolysaccharide (LPS) -induced activation of Nuclear Factor kappa B. This is the first model of this pathway to explicitly include molecular interactions upstream of Nuclear Factor kappa B activation. We produced a formalised graphical depiction of the pathway and built a kinetic model based on ordinary differential equations. The kinetic model accurately reproduced published in vitro time course plots of Lipopolysaccharide-induced Nuclear Factor kappa B activation in mouse embryo fibroblasts. In this preliminary work we have provided proof of concept that it is possible to build computational models of signalling pathways that are relevant to the regulation of labour, and suggest that models that are validated with wet-lab experiments have the potential to greatly benefit the field.
Medical Research Council (MRC) Centre for Reproductive Health, University of Edinburgh, Edinburgh, United Kingdom. Gemma.sharp@ed.ac.uk
Gemma C
GC
Sharp
Hongwu
H
Ma
Philippa T K
PT
Saunders
Jane E
JE
Norman
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D004789:Enzyme Activation; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000235:genetics / Q000378:metabolism*; D047928:Premature Birth / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D013997:Time Factors
D033942:Adaptor Proteins, Vesicular Transport; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C470409:TICAM1 protein, human