Risk vs. Protection: How Microglia Shape Neuronal Survival in Alzheimer’s disease. MRC GW4 BioMed DTP PhD studentship for 2026/27 Entry, Department of Clinical and Biomedical Sciences Ref: 5638

Supervisors

Lead Supervisor:  Dr Thomas Piers - University of Exeter - Department of Clinical and Biomedical Sciences 

Co-Supervisors:  

Dr Daniel Whitcomb  - University of Bristol - Translational Health Sciences, Bristol Medical School 

Dr Sean Flynn - University of Exeter - Department of Clinical and Biomedical Sciences 

The GW4 BioMed2 MRC DTP is offering up to 17 funded studentships across a range of biomedical disciplines, with a start date of October 2026.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 80 students over 4 cohorts in its second phase.

The 122 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

Applications open on 1 September 2025 and close at 5.00pm on 20th October 2025.

Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check our website for details.

Studentships will be 4 years full time. Part time study may also be available.

Project Information

Research Theme: Neuroscience & Mental Health

Summary:

Genetic variants in TREM2 and PLCG2 alter microglial responses in Alzheimer’s disease, but the consequences on neurons remain unclear. This project will use cutting-edge human stem cell models to compare microglia carrying pathogenic versus protective variants, to understand how altered gene regulation affects microglial states and influences neuronal health. The student will combine transcriptomics and functional co-culture assays to uncover how microglia shape neural circuits in disease. This interdisciplinary project offers training in stem cell biology, neuroimmunology, functional neuroscience, and computational biology within a vibrant cross-institutional environment. 

Description:

BACKGROUND 

TREM2 and PLCG2 are critical regulators of microglial activation and function, with genetic variants in both genes linked to Alzheimer’s disease (AD) risk. Rare coding variants in these genes such as TREM2 R47H and PLCG2 P522R represent two ends of the pathogenic-protective spectrum. However, we lack a mechanistic understanding of how these variants alter microglial transcriptional states and how such states influence neurons, particularly in early disease. 

Emerging data suggest that microglia-neuron crosstalk is critical in synaptic maintenance and neuroprotection. This project will use genetically edited human iPSC-derived microglia to model TREM2 and PLCG2 variant effects and assess downstream consequences on neuronal health and function. 

HYPOTHESIS & AIMS 

We hypothesise that AD-associated TREM2 and PLCG2 variants induce distinct regulatory programs in microglia, altering their interaction with neurons and contributing to disease progression. Protective variants may enhance neuro-supportive phenotypes, while pathogenic ones may impair microglial regulation of synapses and neuronal viability. 

Specific aims: 

Aim 1: Generate and characterise isogenic iPSC-derived microglia carrying TREM2 and PLCG2 variants. 

Aim 2: Map transcriptional and epigenetic changes induced by these variants. 

Aim 3: Assess how variant-bearing microglia affect neuronal health, synaptic function, and network activity in co-culture systems. 

Aim 4: Explore pharmacological modulation of variant-induced phenotypes using pathway-specific inhibitors. 

PROJECT DESIGN 

Aim 1 will involve the differentiation of isogenic iPSC lines carrying TREM2 or PLCG2 protective and pathogenic variants into microglia using a defined protocol. The resulting cells will be validated with flow cytometry, immunostaining, and qPCR transcriptomic profiling to confirm microglial identity. 

Aim 2 will generate RNA-seq to identify transcriptional differences between variant-expressing microglia and integrate previously generated epigenomic datasets from the same lines to examine how these variants modulate the gene regulatory landscape in the context of Alzheimer’s disease risk.

Aim 3 will focus on co-cultures of variant microglia and iPSC-derived cortical neurons to assess functional consequences on neuronal health. Neuronal morphology, synapse density, and electrophysiological activity will be monitored to compare the capacity of protective versus pathogenic microglia to support neuronal viability and network connectivity. 

Aim 4 will evaluate whether small-molecule modulators targeting variant-sensitive pathways can alter microglial behaviour in co-cultures. Functional plasticity will be assessed by determining whether pharmacological treatments can shift microglial phenotypes in both directions, from pathogenic toward protective states and vice versa. 

STUDENT OWNERSHIP 

The project is designed to support early and active student involvement. Data generated in Aims 1 and 2, profiling variant-specific transcriptional and epigenetic changes, will guide the student in shaping Aim 3. They will select the most relevant functional assays to assess microglia-neuron interactions. The student will also have the opportunity to choose small molecule modulators to explore in Aim 4, based on pathway insights. Structured mentorship and technical training will be provided by the supervisory team, but the student will be encouraged to make independent decisions and take intellectual ownership of the project’s direction. Cross-institutional visits will enable them to acquire complementary expertise in calcium imaging and electrophysiology. 

OUTCOMES 

This project will provide new insights into how TREM2 and PLCG2 variants influence microglial states and their downstream impact on neuronal function in Alzheimer’s disease. By identifying gene regulatory networks affected by these variants, the work will shed light on conserved pathways of microglial dysfunction. Modelling protective and pathogenic variants in a controlled isogenic system enables mechanistic discovery that extends beyond individual genotypes, offering broader insights into microglial regulation and its role in disease progression. In doing so, the project will inform potential therapeutic strategies to modulate microglial behaviour, with translational relevance for the wider Alzheimer’s population. The findings are expected to support high- impact publications and advance drug discovery in neurodegeneration.

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£20,780 p.a. for 2025/26, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria:

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

If English is not your first language you will need to meet the English language requirements for the University of Exeter by the start of the programme. Please refer to the details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Please check the relevant English Language requirements of the university that will host the PhD project.  

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

If English is not your first language you will need to meet the English language requirements for the University of Exeter by the start of the programme. Please refer to the relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

Please check the relevant English Language requirements of the university that will host the PhD project. 

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 20th October 2025.  Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check the DTP’s website for details and updates

If you are shortlisted for interview, you will be notified from Tuesday, 23rd December 2025.  Interviews will be held virtually on 27th and 28th January 2026.  

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary