About the Project
The project will investigate the control of NF-kB. This transcription factor is one of most important cell signalling systems in the body that controls inflammation and cell fate. When NF-κB is dysregulated it can lead to inflammatory disease or cancer (e.g. various leukaemias, pancreatic breast and prostate cancer). NF-κB signalling involves complex dynamics involving oscillations of the NF-κB complex between the nucleus and cytoplasm in activated cells. These have been compared to Morse code and are believed to carry important information in their timing. This is controlled through feedback loops through several NF-κB inhibitors including IκBα and A20.
We recently showed that the important inflammation regulator A20. plays a particularly important role in the timing of NF-κB translocation. Temperature changes (in the fever range) has been found to affect the timing of NF-κB oscillations and this effect is mediated through A20. A key aim of this project is now to study factors that affect A20 expression and function. Recent data suggests that A20 is expressed in a variable cell context-dependent manner and may be epigenetically regulated.
Micro-RNAs are emerging as key regulators of cellular homeostasis. Several have been shown to regulate NF-κB signalling. miRNAs 125a and 125b are of particular interest, as they have been shown to regulate A20. Our hypothesis is that miRNA regulation of A20 may explain different NF-κB dynamics in different cellular contexts. In addition, the control of miR125 expression by NF-κB may constitute an important new controlling feedback loop that may further regulate the system. Also of great interest is that miR125a and miR125b are often deregulated in cancer (including diffuse lage B cell lymphoma, pancreatic cancer and breast cancer). They also control genes in the Bcl-2 family that are also under NF-κB control and involved in the control of the key step of commitment to apoptosis
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. 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 miRNA 125 a/b control expression of the Bcl-2 family of proteins. The co-supervisor in Manchester, Andrew Gilmore, is an expert on the role of this family in apoptosis commitment
This project offers an opportunity for a student who has an interest in identifying new mechanisms that can lead to new understanding of the causes of important human disease. They will be trained in techniques, including the use of confocal microscopy, fluorescence correlation spectroscopy, RNASeq, qPCR, smRNAFISH, advanced 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.
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.
Chew, CL, Conos, SA, Unal, B and Tergaonkar, V (2018) Noncoding RNAs: Master Regulators of Inflammatory Signaling Trends Mol, Med, 24: 66-84
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