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Analysis of the role of microRNAs in the regulation of NF-kappaB dynamics and function


Project Description

NF-κB is one of most important cell signalling systems in the body and controls inflammation and cell fate. NF-κB signalling involves complex dynamics involving oscillations of the NF-κB complex between the nucleus and cytoplasm in activated cells. This is controlled through feedback loops through inhibitors including IκBα and A20. Micro-RNAs are key regulators of cellular homeostasis. miRNAs 125a and 125b regulate A20 and the control of miR125 expression by NF-κB may constitute an important new regulatory feedback loop. They are often deregulated in cancer. They also control the Bcl-2 family of proteins that control commitment to apoptosis.
The student will:
1). Investigate the control of A20 and miRNAs miR125a and miR125b in cell types that show markedly varying dynamics. These will include human neuroblastoma SK-N-AS cells, HeLa cells and normal human breast MCF10A cells. We will use single molecule RNA FISH to quantify these levels of these RNAs. We will use lentivirus transfection and CRISPR to express A20- fluorescent fusion proteins and fluorescent correlation spectroscopy and quantitative western blotting to quantify A20 protein levels.
2) Investigate the role of the microRNAs by perturbing their gene expression using both CRISPR and overexpression strategies. This will include development of inducible systems using lentiviruses and possible we will investigate the use of optogenetic control of Cas9.
3) Perform genomic screens of the expression of these and other candidate microRNAs in a variety of cell lines and primary cells. We will investigate the global gene expression consequences of perturbation of expression of the microRNAs on global gene expression and the pattern of NF-κB expression that results.
4) Investigate the effect of NF-κB and miR125a and MiR125b on apoptosis commitment in different cell contexts. Our hypothesis is that these microRNAs may play a role in determining the role of NF-κB signalling in apoptosis commitment.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/ subject. Candidates with an interest in cell signalling, cell biology and cell imaging are encouraged to apply. We would consider a mathematician who required training in biology. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. For UK/EU tuition fees are £15,000 and International are £29,500 for 2018/19 academic year.

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

D.E. Nelson, A.E.C. Ihekwaba, M. Elliott, J. Johnson, C.A. Gibney, B.E. Foreman, G. Nelson, V. See, C.A. Horton, D.G. Spiller, S.W. Edwards, H.P. McDowell, J.F. Unitt, E. Sullivan, R. Grimley, N. Benson, D. Broomhead, D.B. Kell & M.R.H. White. (2004) Oscillations in NF-κB signaling control the dynamics of gene expression. Science 306: 704-8.

Ashall L, Horton CA, Nelson DE, Paszek P, Harper CV, Sillitoe K, Ryan S, Spiller DG, Unitt JF, Broomhead DS, Kell DB, Rand DA, Sée V & White MRH. (2009) Pulsatile stimulation determines timing and specificity of NF-kappa B-dependent transcription. Science, 324: 242-246.

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-E5249.

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.

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