Understanding the role of RNA binding proteins in the regulation of NF-kappa B dynamics, inflammation and cell death

NF-kB is a key signalling system that controls inflammation and cell fate, dysregulation of which can lead to inflammatory disease or cancer. NF-kB signalling is complicated and not fully understood. The NF-kB 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-kB signalling. A number of NF-kB inhibitors are involved in regulation of this timing, including IkBa and A20.
We are particularly interested in the inflammation regulator A20, which plays an important role in the timing of NF-kB translocation. Temperature changes (in the fever range) have been found to affect the timing of NF-kB 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.
RNA binding proteins and microRNAs are emerging as key regulators of cellular homeostasis. The RNA binding protein TTP/ZFP36 (and its paralogs), and miRNAs 125a and 125b can regulate A201,2. Our hypothesis is that regulation of A20 RNA stability and translation may explain different NF-kB dynamics in different tissues. Our preliminary data suggest that the control of ZFP36 and miR-125 expression by NF-kB may represent important new feedback loops that further regulate the NF-kB system.
The student will work between labs with expertise in NF-kB signalling, bioinformatics and cell fate. Mike White has built many tools for the analysis of NF-kB dynamics in cells and tissues. Andrew Gilmore works on the control of cell death and the role of the Bcl-2 family of proteins, and has extensive experience in molecular and cell biology and gene editing. Sam Griffiths-Jones is a world expert on microRNAs and bioinformatics. Mark Muldoon provides mathematical modelling.
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 techniques, including advanced (e.g. confocal) microscopy, fluorescence correlation spectroscopy, RNASeq, qPCR, smRNAFISH, proteomics, CRISPR, lentivirus manipulation and bioinformatics.
1. Tiedje, et al., (2016) The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation Nucleic Acids Research, 44: 7418-40,
2. Kim, et al., (2012) MicroRNAs miR-125a and miR-125b constitutively activate the NF-kB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20). PNAS 109: 7865-70.
The student will be trained in molecular cell biology, physiology, genomics, biochemistry, advanced microscopy, genetic manipulation by CRISPR and lentiviral transduction. They would also be trained in bioinformatics and have the opportunity to be trained in mathematical modelling through working alongside theoreticians (Collaborative support on modelling with longstanding collaborators in Manchester and Warwick). The project would involve a collaboration with Dr Martin Turner, ISP lead for Immunology, Babraham Institute, a BBSRC Institute. The training fits BBSRC ENWW priorities in bio-imaging (M. White co-author of BBSRC bio-imaging report) and systems biology. The work on the project is relevant to understanding healthy ageing, a BBSRC priority area and studies fundamental mechanisms of control of gene expression and cell fate. This is relevant to the normal control of inflammation as well as aetiology of inflammatory disease and cancer.
The student will have the opportunity to take part in training courses (Zeiss sponsored microscopy courses and BBSRC initiated SYSMIC online mathematical modelling training). They would work in an environment where cross-disciplinary teamwork is the norm, a BBSRC training priority identified in the BBSRC people and training report