Type 1 diabetes (T1D) is caused by the selective destruction of insulin producing beta-cells. This process is mediated by autoreactive immune cells which erroneously target beta-cell proteins. Immune cells detect their targets through interaction with the major histocompatibility complex class I (MHC-I) which is found on the surface of all cells. However, the levels of this complex are dramatically increased on beta-cells during T1D development, thereby increasing the visibility of these cells to the immune system and expediting disease progression. Thus, targeting of the mechanisms which underpin MHC-I ‘hyper-expression’ may be beneficial to individuals with T1D.
We have studied the signalling processes which regulate MHC-I and have discovered that interferons (IFN) released during diabetes pathogenesis play an important role in elevating MHC-I levels. Moreover, we have pinpointed a transcription factor, STAT1, as a central player in this process. STAT1 activity is thought to be primarily controlled by phosphorylation, however recent data suggest that acetylation may also be a key regulator of this process. In support of this we have shown that inhibitors of enzymes which promote deacetylation of proteins (histone deacetylases (HDAC)), can prevent the phosphorylation and activation of STAT1. During this PhD the student will explore whether broad spectrum HDAC inhibitors already in clinical usage can impede IFN signalling and subsequent MHC-I upregulation in beta-cells. These data will inform whether these drugs could be repurposed as a T1D treatment.
To achieve this goal the student will use a range of molecular biology approaches to forensically study the impact of the HDAC inhibitors on IFN signalling and MHC-I expression, including; Western blotting, flow cytometry, quantitative PCR, co-immunoprecipitation and dual-luciferase reporter assays. An additional objective will be to identify the specific HDAC isoform(s) responsible for mediating these effects. Here, small interference RNA will be used to deplete specific HDAC isoforms to determine whether they are capable of STAT1 deacetylation. Finally, the expression of the HDACs responsible will be examined in human pancreas sections, including those from people with T1D.
The student will join the active Islet Biology Exeter (IBEx) research team in the state-of-the-art RILD laboratories situated on the Royal Devon and Exeter Hospital site. IBEx have extensive experience in the study of pancreatic islets and the signalling pathways which regulate beta-cell viability. In house training will be provided for all laboratory techniques, but the student will have access to additional training opportunities over the life cycle of the PhD.
NIHR Exeter BRC Commitment
This Studentship will be nested within the National Institute of Health and Care Research Exeter Biomedical Research Centre (NIHR Exeter BRC), hosted by the Royal Devon University Healthcare NHS Foundation Trust in partnership with the University of Exeter and in collaboration with South West NHS organisations. The first of its kind for the South West peninsula, the Centres fundamental objective is to improve health outcomes for patients and the public by translating scientific breakthroughs into potential new treatments, diagnostics and medical technologies.
This studentship will provide the opportunity to work with world-leading researchers and have access to state-of-the-art facilities. The NIHR Exeter BRC are committed to developing and nurturing a diverse and rich pipeline of talented researchers by equipping them with the knowledge and skills to excel and contribute significantly to the local and national economy via the delivery of high-quality and impactful translational biomedical research. Expertise will be harnessed from across the partnership to deliver the best possible training and career development opportunities, with the student provided the opportunity to be embedded in a rich research culture, with a growing body of early career researchers.
We are delighted to have already recruited some exceptionally talented researchers at various career stages to our NIHR Exeter BRC, including Senior Investigator Fellows, Translational Fellows and our first cohort of PhD students who started with us in September.
It should be noted that funding will not allow all projects to be appointed to, as such, the top performing candidates as chosen by the selection panels will be matched to their project of choice and only these will be awarded. You are able to apply for up to two projects being advertised within this funding round.
Fees and funding
For eligible students, the studentship will cover Home tuition fees plus an annual tax-free stipend of at least £18,622 (in alignment with standard Research Council UK rate) for 3 years full-time, or pro rata for part-time study, in addition to a Research Training and Support Grant (RTSG). The student would be based at the Research, Innovation, Learning and Development (RILD) building based at the Royal Devon and Exeter Hospital site in Exeter, near to the St Luke’s campus.
*Students who pay international tuition fees are eligible to apply, but should note that the award will only provide payment for part of the international tuition fee and no stipend. International applicants need to be aware that you will have to cover the cost of your student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.
The conditions for eligibility of home fees status are complex and you will need to seek advice if you have moved to or from the UK (or Republic of Ireland) within the past 3 years or have applied for settled status under the EU Settlement Scheme.
The closing date for applications is midnight on Tuesday 2nd January 2024.
Interview panels will be held virtually in late January/ early February 2023 for a September 2024 start.
If you would like to discuss the studentships further, please contact the primary supervisor as stated in the advert. If you have any queries surrounding the application process or the BRC more generally, please contact Dr Sophie Gould (NIHR Exeter BRC Training and Events Manager) at [Email Address Removed].
Applicants for this studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate subject area.