Biological ageing can be thought of as a progressive decline in the ability of an organism to survive stress and disease. It is a complex process which is influenced by both genetic and environmental factors. Yeast cells have been increasingly used as a model of ageing and have significantly contributed to our understanding of numerous conserved ageing genes and signalling pathways. Yeast cells can survive for prolonged periods of time in culture and have been used as a model of the chronological life span (CLS) of mammals, particularly for tissues composed of non-dividing populations. In the CLS model, populations of stationary phase cells are maintained in liquid and various physiological parameters, such as viability, replication ability and metabolism, measured over time. Studies using this model have identified many key conserved ageing factors that modulate ageing. Translational activity is maintained in quiescent stationary phase cells, albeit at a much reduced rate compared with proliferating cells. However, very little is known about how translation is maintained in aged cells compared with actively growing cells, and whether mRNA-specific translation influences longevity. This project will use a multidisciplinary approach to define the role of translational regulation during ageing. The key question to be addressed in this project is whether mRNA specific translation influences ageing, and if so, can altering translational activity moderate longevity
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a Biological science. Candidates with experience in molecular biology and an interest in gene expression are encouraged to apply.
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
This project combines traditional yeast molecular biology and genetic approaches with next generation sequencing techniques and high-end microscopy. The project will use next-generation sequencing approaches to study mRNA-specific translational control mechanisms during ageing. Microscopy will be used to study how ageing-specific mRNAs localize to specific intracellular ribonucleoprotein (RNP) granules which are formed from RNA and RNA-binding proteins. Extensive yeast genetic approaches will be used to validate and extend the findings from these technically demanding approaches. The project data will require extensive bioinformatic and statistical analyses aimed at identifying alterations in translational regulation ageing during chronological ageing.
Costello, J., Castelli, L. M., Rowe, W., Kershaw, C. J., Sims, P. F. G., Grant, C. M., Pavitt, G. D., Hubbard, S. J., and Ashe, M. P. (2015) Global mRNA selection mechanisms for translation initiation. Genome Biol. 16: 10.
Castelli, L.M., Talavera, D., Kershaw, C.J., Mohammad-Qureshi, S.S., Costello, J.L., Rowe, W., Sims, P.F., Grant, C.M., Hubbard, S.J., Ashe, M.P. and Pavitt G.D. (2015) The 4E-BP Caf20p mediates both eIF4E-dependent and independent repression of translation PLOS Genet. 11: e1005233.
Lawless, C., Holman, S.W., Brownridge, P., Lanthaler, K., Harman, V.M., Watkins, R., Hammond, D.E., Miller, R.L., Sims, P.F., Grant, C.M., Eyers, C.E., Beynon, R.J., and Hubbard SJ (2016) Direct and Absolute Quantification of over 1800 Yeast Proteins via SRM. Mol Cell Proteomics. 15:1309-22
Costello, J.L., Kershaw, C.J., Castelli, L.M., Talavera, D., Rowe, W., Sims, P.F.G., Ashe, M.P., Grant, C.M., Hubbard. S.J., and Pavitt, G.D. (2017) Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses. Genome Biol. 27; 18: 201.
Jarnuczak, A. F., Albornoz, M.G., Eyers, C.E., Grant, C.M. and Hubbard, S.J. (2018) A quantitative and temporal map of proteostasis during heat shock in Saccharomyces cerevisiae. Mol. Omics, 14: 37-54.