Supervisors: Lyndsay Murray, Thomas Wishart
Project Description:
It is well known that neurons can be targets of a range of pathological, chemical or traumatic stimuli. A common feature observed is the vulnerability of the axonal and synaptic compartments of the cell. Axon and synaptic degeneration is often one of the earliest anatomical changes occurring following injury or during disease. It is therefore important that we investigate the cellular mechanisms which regulate the degeneration of synapses and axons. Interestingly, the process of axon degeneration in response to injury is slower in mice aged under 3 weeks, compared to adults (Murray et al., 2011). In order to investigate the molecular mechanisms underlying this delay, we performed cutting edge tandem mass-tagging comparative quantitative proteomics to profile both nerve and muscle at 5 time points covering the duration of this critical time window. This analysis has provided unprecedented insight into the nerve muscle proteome, profiling over 6000 proteins across 5 time points. Preliminary analysis of this data reveals a continuous upregulation of proteins involved in mRNA processing and RNA binding in nerve. There is also a continuous upregulation of proteins involved with the endoplasmic reticulum and protein transport in muscle. The impact that these changes have upon axon degeneration and upon normal postnatal development of the neuromuscular system are unclear.
In this project, you will first apply powerful pathway analysis software to this proteomic data (Llavero et al., 2017). You will combine analysis of molecular networks to identify key changes occurring in the muscle and nerve during post-natal development. You will then use standard cell biology techniques to validate these changes and investigate any functional changes which correlate with the molecular pathways identified. Finally, you will use an ex-vivo model of axon injury to explore the impact that these changes have upon the rate of axon degeneration and the vulnerability of the neuromuscular system.
References:
Llavero Hurtado, M., Fuller, H.R., Wong, A.M.S., Eaton, S.L., Gillingwater, T.H., Pennetta, G., Cooper, J.D., Wishart, T.M., 2017. Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo. Sci Rep 7, 12412.
Murray, L.M., Comley, L.H., Gillingwater, T.H., Parson, S.H., 2011. The response of neuromuscular junctions to injury is developmentally regulated. FASEB J 25, 1306-1313.
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