1. Dynamics and function of the NF-kB signalling system

(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.

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 2. Eukaryotic G protein-mediated signalling

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.

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