Targeting protein acetylation to reduce microglia activation in neurodegenerative disorders

About the Project

The School of Biomedical Sciences invites applications from prospective postgraduate researchers who wish to commence study for a PhD in the academic year 2025/26.

This opportunity is open to candidates who have the means to self fund their studies or who have a sponsor who will cover this cost.

We will target protein acetylation to reduce microglia activation as a potential therapy for Alzheimer’s and neurodegeneration.

Recently, inhibitors of histone deacetylase enzymes (HDACs) have been identified as having potential therapeutic value for a range of neuronal disorders including Alzheimer’s disease, dementia and stroke. The HDAC inhibitors have been shown to have neuroprotective and anti-inflammatory properties yet their mechanism of action remains unidentified. We have recently shown that microglia activation by a number of insults (eg Amyloid beta, LPS and interferon) can be reduced by HDAC inhibitors. Using siRNA we have identified HDAC1 and HDAC2 as the important HDAC enzymes for this response. Whilst still don’t know the mechanism by which HDAC inhibitors block microglia activation we have shown that it doesn’t require new protein synthesis so is unlikely to be a result of the well characterised effect of these inhibitors on increasing gene expression. We are currently investigating the cellular mechanism(s) involved in the inhibition and identifying the molecular targets involved. Current HDAC inhibitors are non-selective and their long-term use is thought to impair cognition due to widespread off target effects and identifying the mechanism by which they reduce excessive microglia activation would open up novel therapeutic targets for the treatment of neurodegenerative disorders.

We have a number of candidate proteins that are known to be involved in regulating microglia activation and are modulated by acetylation. We plan to test these candidates and we are currently performing a screen of all microglia proteins to identify which proteins are differentially acetylated in response to microglia activation and HDAC inhibition which should provide novel targets to characterise. The project will involve the use of cell culture methods of primary and immortalised microglia, functional assays to quantify cell responses such as proliferation, apoptosis and migration as well as biochemical and molecular approaches to quantify cytokine production (ELISA) and changes in gene and protein expression (RT-PCR, western, immunofluorescence).

Eligibility

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Biological Sciences minimum requirements in IELTS and TOEFL tests are:

• British Council IELTS - score of 6.0 overall, with no element less than 5.5
• Internet based TOEFL - overall score of 80 with not less than 17 in listening, 18 in reading, 20 in speaking and 19 in writing. Tests must be taken at a test centre.

How to apply

To apply for this project applicants should complete an online application form and attach the following documentation to support their application.

• a full academic CV
• degree certificate and transcripts of marks
• Evidence that you meet the University's minimum English language requirements (if applicable)
• Evidence of funding

To help us identify that you are applying for this project please ensure you provide the following information on your application form;

• Select PhD in Biological Sciences as your programme of study
• Give the full project title and name the supervisors listed in this advert

For more information about this project please contact Professor Ian Wood:

e: i.c.wood@leeds.ac.uk

https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/158/professor-ian-wood

For information about the application process please contact the Faculty Admissions Team:

e: fbsgrad@leeds.ac.uk