(Funding includes approx. £5million SABR grant, led by M White (Liverpool), Rand directs the theory.)
- Develop and apply a set of quantitative experimental tools coupled to an intensive theoretical analysis to properly analyse the dynamic function of the NF-κB signalling system
How do the complex feedback loops controls NF-κB dynamics and downstream gene expression? How do cells achieve appropriate cell fate decisions in response to time-varying signals?
Experimental work will integrate dynamic cell and single molecule imaging, quantitative proteomics, chromatin immunoprecipitation analysis (for the dynamics of NF-κB binding to target promoters) and RT-PCR and DNA microarray analysis (for measurement of endogenous gene expression).
Theoretical work will develop: (a) new data analysis tools to interpret and direct experimental strategy, (b) deterministic and (c) stochastic mathematical models of the system.
WSB Staff: Finkenstadt (Statistics), Rand, Ott.
Collaborators: (Liverpool) Michael White Violaine Sée, Pawel Paszek, Rachel Bearon, Chris Sanderson, Rob Beynon, Claire Harper, David Spiller, Raphaël Lévy (Manchester) Dean Jackson, Douglas Kell, David Broomhead, Norman Paton, Simon Gaskell, Alvaro Fernandes, Chris Taylor, George Reid (EMBL)
Recent work in G Ladd’s laboratory, MOAC (Ben Smith) and WSB has:
indicated that GTP hydrolysis arising from ligand activation of a GPCR, far from being solely responsible for desensitisation, is essential if cells are to achieve their maximal signalling output
developed a qualitative computational model that informs our in vivo experimentation and predicts the existence of a novel Ga subunit intermediate that is bound to GTP, but is inactive
identified a new generic dynamic motif that we wish to test against G protein-mediated signalling networks in all eukaryotes.
This project aims:
to verify the existence of this state; and
continue a systems biology approach to utilise state-of-the-art in vivo experimental techniques to generate kinetic data so producing a quantitative model, thereby increasing its accuracy for informing experimental design.
PeopleWSB Staff: Ladds, Rand, van den Berg, Davey
Collaborators: Ben Smith (Warwick, MOAC student)