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Immunoproteasomes as novel therapeutic targets in neurodegenerative disorders

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Applications are invited for a 3.5 year PhD studentship in the UK DRI Centre at Imperial in the research group of Dr Yu Ye (https://www.imperial.ac.uk/people/yu.ye1).

The project is based at Imperial’s new White City Campus, the Hub for convergent research.

The UK Dementia Research Institute: There are currently around 850,000 people with dementia in the UK. This is projected to rise to 1.6 million by 2040. The UK DRI at Imperial has been established to address a medical research area of the highest importance and future impact. As one of seven national centres of excellence embedded in major UK universities, we intend to transform the diagnosis, treatment and care of people with dementias. The Medical Research Council and charity partners the Alzheimer's Society and Alzheimer’s Research UK have invested £290m in fulfilment of the ambition identified in the Prime Minister's 2020 Challenge on Dementia.

The laboratory

The fellowship programme of Dr Yu Ye is focused on interplay between the ubiquitin-proteasome system (UPS) and amyloid proteins in biological systems. Using advanced fluorescence imaging techniques, the lab seeks to uncover the biochemical and cellular mechanisms of restricting or reversing protein aggregation, and how malfunction of the UPS system leads to neurodegenerative disorders.

Background

Proteasomes are abundant molecular recycling machines that are responsible for selective protein degradation. During stress and inflammation, standard proteasomes are modified into so-called immunoproteasomes (iPs), which are activated by inflammatory cytokine such TNF-alpha and IFN-gamma. Importance of iP functions are only beginning to be explored as innovative and entirely novel therapeutic strategies to regulate neurodegeneration and dementia. Immunoproteasome upregulation has been correlated with chronic neuroinflammation and found activated in the glial cells surround plaques in AD patients. Possibly, iPs could also target aggregates of amyloid proteins, as we have shown with standard proteasomes. Controlling specific proteasome types and their distinct functions is an unexplored and potentially promising therapeutic strategy to delay or reverse neurodegenerative conditions. Selective targeting of proteasome functions could both limit formation of the harmful amyloidogenic agents causing neuronal death as well as preventing neuroinflammation.

The project

This project studies mechanisms of immunoproteasomes (iP) that cause chronic neuroinflammation and neuronal degeneration, leading to Alzheimer’s (AD) and Parkinson’s disease (PD). Based on previous observations in tissues, the project will identify whether aggregates interact with iP and how this affect iP activity and function that could lead to sustained inflammation. A separate approach is to identify consequences of iP function in microglia, astrocytes and neurons are stimulated during aggregate spreading and its consequences to neuroinflammation. The research will benefit from advanced imaging systems, genetic engineering approaches and established proteasome protocols in the Ye lab. Ultimately, the project will identify novel pathways and distinct targets key to delay/reverse neurodegeneration.

Studentship Details

Students will be registered in the Department of Brain Sciences in the Faculty of Medicine.
Applicants must hold (or obtain by October 2020) a First Class or an Upper Second Class degree (or equivalent overseas qualification) in a Biological Sciences / Neuroscience or related discipline, and Imperial would normally expect successful applicants to hold or achieve a Master's degree in a related field. Prior experience in ubiquitin-proteasome system is not essential but experience with biochemical, cell biology and microscopy techniques would be preferred.

For informal enquiries please contact Dr Yu Ye (). For application, please send a full CV, stating your nationality, and the full contact details of two academic referees. We regret that due to the large volume of applications received, we are only able to notify those shortlisted for interview. Applications will be considered throughout the year.

Funding Notes

The award is for 42 months (full time) and covers course fees at the Home/EU rates (2020/21 fees £6,300 per annum) and a tax-free stipend starting at £19,000 per annum.
Non-EU applicants, if successful, will be responsible for payment of fees at the overseas rate (currently £39,600 per annum). Funding for overseas fees is not provided.

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