Funded PhD Projects
The following PhD projects come with funding (at the time of writing) to cover tutition fees and living expenses. Please note that they may not be available to students from outside the UK or the European Union. We strive to keep this page up to date, but please contact the supervisor of any PhD opportunity you wish to apply for. They will be able to provide current information on any funding restrictions. A more extensive list of projects, both with and without funding, is available.
|Screening of chemical libraries using iPS models for investigating the role of prion protein in Alzheimer’s disease||
AD has been identified as a protein misfolding disease (proteopathy). The disease is caused by accumulation of two major amyloids: a rounded “amyloid plaque” outside cells and “neurofibrillary tangles” inside cells. A number of theories have been developed to describe the cause and characteristics of AD although the exact cause is still not fully understood.1,2,3,4,5
Recently, it has been reported that cellular prion protein, PrPC, binds to Aβ1-42 oligomer and inhibits the long-term potentiation (LTP) in mice.6 Antibodies targeting the 94-104 region in PrPC blocks the inhibition of LTP triggered by soluble Aβ1-42 oligomer.7,8 PrPC has also been reported to affect the formation of the Aβ oligomers by modulating the function of β-secretase (BACE-1).9
Fig. 1 Suggested role of prion protein, PrPc, in Alzheimer's disease. PrPc binds, regulates activity of BACE in cleavage of amyloid precursor protein (APP); PrPc acts as receptor for Aβ dimer. PrPc forms a complex with Fyn (probably with the help of Cav-1); and the complex regulates Tau hyperphosphoration, hence Tangle formation.
The close relationship amongst PrPC, Aβ and Tau was unveiled in recently studies. It was found that PrPC is enriched in postsynaptic densities, and the Aβ-PrPC interaction leads to activation of the Src tyrosine kinase Fyn and neuronal demise.11 Aβ engagement of PrPC-Fyn signalling yielded phosphorylation of the NR2B subunit of NMDARs. Fyn can mediate Aβ/Tau-induced toxicity.12 New evidence has showed that soluble Aβ and the Aβ1-42 dimer in particular can bind to PrPC at neuronal dendritic spines where it forms a quadruple complex with Fyn via Cav-1. This results in the activation of the Fyn kinase, which in turn triggers aberrant missorting and hyperphosphorylation of Tau, hence tangle formation.13,14 (Figure 1)
Henceforth, PrPC seems to be an important piece of the jigsaw in the AD landscape. Together with the amyloid and Tau theory, it could provide solutions to some unsolved questions in AD aetiology. Understanding the role PrPC in AD is extremely important and could shine lights on developing new diagnostics and drugs to combat AD.
Aims and Objectives
The aims of the project are:
Year 1 - Develop and optimise iPS cellular model from epithelium cells from healthy and Alzheimer patient
Epithelium cells from healthy and Alzheimer patients will be reprogrammed and then differentiated into young neurons and cortical neurons and level of expression of PrPC and its interacting partners will be assessed using Western blotting and ICC and flow cytometry.
Year 2 - Study the interaction between PrPC and its interacting partners such as A, mGlu5, and NMDAR etc; screen chemical libraries for compounds interfering the interactions
Pairwise interaction studies between PrPC and its interacting partners will be carried out using doubly labelled fluorescence tags and the ability of small molecules in interfering such interactions will be assess. Hit compounds will be selected for further studies.
Year 3 - Investigate the mode-of-action of initial hits
The mode-of-action of selected hits will be thoroughly studied using a range of techniques such as RNAi screening and pull-down assays.
For more information
1Braak, H ; Braak, E ; 1991. Acta Neuropathlogia, 82(4): 239-259;