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(A*STAR) Analysis of the role of microRNAs in the regulation of NF-kappaB dynamics and function


Project Description

NF-κB is a key signalling system that controls inflammation and cell fate, dysregulation of which can lead to inflammatory disease or cancer. NF-κB signalling is complicated and not fully understood. The NF-κB complex shuttles between the nucleus and cytoplasm in activated cells. The timing of this movement is believed to be critical to the outcome of NF-κB signalling. A number of NF-κB inhibitors are involved in regulation of this timing, including IκBα and A20.

We are particularly interested in the inflammation regulator A20, which plays an important role in the timing of NF-κB translocation. Temperature changes (in the fever range) have been found to affect the timing of NF-κB oscillations, and this is mediated through A20. Recent data suggests that A20 expression varies greatly from cell to cell. It is therefore important to understand factors that control A20 expression and function at the single cell level.

MicroRNAs are emerging as key regulators of cellular homeostasis. miRNAs 125a and 125b are known to regulate A20. Our hypothesis is that regulation of A20 RNA stability and translation may explain different NF-κB dynamics in different tissues. Our preliminary data suggest that miR-125 expression by NF-κB may represent important new temperature-sensitive feedback loops that further regulate the NF-B system. This may represent an opportunity for the manipulation of this system to manipulate inflammatory responses and cell fate decisions (e.g. in cancer therapy).

The student will work between expert labs in Manchester and Singapore with considerable experience in NF-κB biology in both centres. The Manchester laboratory of Mike White has built many tools for the imaging of NF-κB dynamics in cells and tissues and the student will be trained in state of the art cell imaging. The Singapore laboratory of Vinay Tergaonkar has considerable expertise in genomics and proteomics, as well as expertise in studying micro RNAs. A co-supervisor in Manchester, Sam Griffiths-Jones, is a world renowned expert on miRNAs and bioinformatics. The student would be trained in advanced genetics and genomics. In addition, the student will study a range of cancers to characterise the status of these regulatory genes. A particular focus will be the regulation of apoptosis as both NF-κB and miRNA125a/b control expression of the Bcl-2 family of proteins. The other co-supervisor in Manchester, Andrew Gilmore, is an expert on the role of this family in apoptosis commitment.

This project offers an outstanding opportunity for a student who has an interest in identifying new fundamentally important mechanisms that can lead to new understanding of the causes of important human disease. They will be trained in advanced techniques, including advanced (e.g. confocal) microscopy, fluorescence correlation spectroscopy, RNASeq, qPCR, smRNAFISH, proteomics, CRISPR, lentivirus manipulation and bioinformatics.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Nelson, D.E., Ihekwaba, A.E.C., Elliott, M., Johnson, J., Gibney, C.A., Foreman, B.E., Nelson, G., See, V., Horton, C.A., Spiller, D.G., Edwards, S.W., McDowell, H.P., Unitt, J.F., Sullivan, E., Grimley, R., Benson, N., Broomhead, D.S., Kell D.B. & White, M.R.H. (2004) Oscillations in NF-κB signaling control the dynamics of gene expression. Science 306: 704-8.
Ashall, L., Horton, C.A., Nelson, D.E., Paszek, P., Harper, C.V., Sillitoe, K., Ryan, S., Spiller, D.G., Unitt, J.F., Broomhead, D.S., Kell, D.B., Rand, D.A., Sée, V. & White M.R.H. (2009) Pulsatile stimulation determines timing and specificity of NF-kappa B-dependent transcription. Science, 324: 242-46.
Harper, C. V., Woodcock, D. J., Lam, C., Garcia-Albornoz, M., Adamson A., Ashall, L., Rowe, W., Downton, P., Schmidt, L., West, S., Spiller, D. G., Rand, D. A. & White, M. R. H. (2018) Temperature regulates NF-κB dynamics and function through timing of A20 transcription. Proc. Natl. Acad. Sci. USA, 115: E5243-49.
Adamson, A., Boddington, C., Downton, P., Rowe, W., Bagnall, J., Lam, C., Maya-Mendoza, A., Schmidt, L., Harper, C.V., Spiller, D.G., Rand, D.A., Jackson, D.A., White, M.R.H., & Paszek, P. (2016) Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states. Nat. Comm. 7: e12057.
Chew, CL, Conos, SA, Unal, B and Tergaonkar, V (2018) Noncoding RNAs: Master Regulators of Inflammatory Signaling Trends Mol, Med, 24: 66-84
Kim SW, Ramasamy K, Bouamar H, Lin AP, Jiang D, Aguiar RC. (2012) MicroRNAs miR-125a and miR-125b constitutively activate the NF-κB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20). Proc Natl Acad Sci U S A. 109: 7865-70.
Schellenberg, B., Wang, P., Keeble, J. A., Rodriguez-Enriquez, R., Walker, S., Owens, T. W., Foster, F., Tanianis-Hughes, J., Brennan, K., Streuli, C. H., and Gilmore, A. P. (2013) Bax Exists in a Dynamic Equilibrium between the Cytosol and Mitochondria to Control Apoptotic Priming. Mol Cell. 49, 959–71.

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