Communication Breakdown: Using human assembloid models to understand disruption of neuron-glia interactions in ALS. MRC GW4 BioMed DTP PhD studentship for 2026/27 Entry, Department of Clinical and Biomedical Sciences Ref: 5627

Supervisors

Lead Supervisor: Dr Akshay Bhinge - University of Exeter - Living Systems Institute - Department of Clinical and Biomedical Sciences 

Co-Supervisors:

Dr Yasir Syed - Cardiff University - School of Biosciences

Dr Magdelana Strauss - University of Exeter - Department of Mathematics and Statistics 

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:  

ALS is a devastating neurological disease with no cure, and we urgently need new ways to understand and treat it. This exciting PhD project combines cutting-edge stem cell technology, 3D brain cell models, and advanced genomic analysis to explore how nerve cells and support cells interact in health and disease. You’ll model a key ALS feature seen in most patients and use high-resolution single-cell techniques and drug screening to uncover new disease mechanisms and drug candidates. This highly interdisciplinary and collaborative project offers exceptional training in neuroscience, genomics, bioinformatics and translational research. 

Details:

Amyotrophic lateral sclerosis (ALS) is a devastating, progressive neurodegenerative disorder marked by the selective loss of motor neurons (MNs). Patients typically experience increasing immobility, paralysis, and ultimately succumb to respiratory failure within 3–5 years of diagnosis. Despite decades of research, effective treatments remain limited. A deeper understanding of the molecular and cellular events leading to MN degeneration is urgently needed to develop effective therapeutic strategies.

Approximately 85% of ALS cases are sporadic (sALS), while 15% are familial (fALS) and linked to known genetic mutations. A consistent molecular hallmark across nearly all ALS cases is the mislocalization of TDP-43, a nuclear RNA-binding protein involved in splicing and other aspects of RNA metabolism. In ALS, TDP-43 abnormally accumulates in the cytoplasm, resulting in a loss of its nuclear function and widespread splicing defects. These aberrant splicing events often produce truncated, dysfunctional proteins, particularly in genes essential for neuronal health.

While MNs are the primary cells affected, there is growing recognition that ALS is a non-cell-autonomous disease. Glial cells, including oligodendrocytes and microglia, play essential roles in maintaining neuronal homeostasis and have been implicated in disease progression through mechanisms such as neuroinflammation and metabolic dysregulation. However, the dynamic interplay between these cell types—especially how glia contribute to MN degeneration—remains poorly understood.

This project aims to investigate neuron-glia interactions in the context of ALS, using cutting-edge human stem cell-derived models and genomics. Specifically, it will examine how TDP-43 mislocalization impacts intercellular communication and contributes to neurodegeneration. The findings will provide novel insights into non-cell-autonomous mechanisms and may identify new targets for therapeutic intervention. We will utilize induced pluripotent stem cells (iPSCs) to generate MNs, microglia, and oligodendrocytes. To model TDP-43 pathology without introducing mutations or external stressors, we will employ a novel system developed in-house that induces cytoplasmic mislocalization of endogenous TDP-43, closely mimicking the molecular phenotype of sporadic ALS.

Specific Objectives

1.  Develop a human iPSC-derived assembloid model of ALS

The student will generate spinal MNs, oligodendrocytes, and microglia from iPSCs using established differentiation protocols optimized in the Bhinge and Syed labs. These cells will be assembled into 3D co-cultures ("assembloids") by combining them in varying ratios to determine optimal conditions for cellular organization and function. Assembly will be performed using low-attachment plates and centrifugation to promote aggregation.

Different assembloid configurations—with and without specific glial populations—will be compared to assess the contribution of each cell type to MN health. Over a four-week period, the student will perform detailed phenotypic characterization, including assessments of neuronal survival, neurite outgrowth, synapse formation, oligodendrocyte maturation, and microglial activation via immunostaining.

Student ownership: The student will take a leading role in optimizing co- culture conditions, selecting relevant functional assays, and interpreting phenotypic outcomes.

2.  Characterize the assembloid model using single-cell transcriptomics To dissect molecular changes at the cellular level, single-cell RNA sequencing (scRNA-seq) will be performed on assembloids and simpler co-cultures (e.g., neuron-glia pairs). This will allow precise mapping of transcriptomic alterations in each cell type and the identification of cell- type-specific responses to TDP-43 pathology.

The student will conduct ligand-receptor interaction analyses to explore how intercellular communication is disrupted. Network analysis will identify key regulatory genes and pathways affected by TDP-43 mislocalisation. Long-read Oxford Nanopore sequencing will be used to detect splicing abnormalities, including CE inclusion, associated with TDP-43 dysfunction.

Dr. Strauss will provide expert guidance on the bioinformatic analysis of single-cell transcriptomic data, including clustering, differential gene expression, pathway analysis, and cell-cell communication modelling.

Their support will ensure robust interpretation and integration of the transcriptomic datasets.

3.  Identify and test candidate therapeutics to reverse ALS phenotypes Transcriptomic signatures from TDP-43 assembloids will be compared against the Broad Institute’s Connectivity Map (CMap), which profiles the transcriptional effects of over 1,300 bioactive compounds. Compounds whose expression signatures are inversely correlated with disease profiles will be shortlisted as potential therapeutic candidates. Top candidates will be tested in vitro using the iPSC-derived assembloids. The student will evaluate the efficacy of these compounds in rescuing ALS-associated phenotypes using both immunocytochemistry and scRNA-seq. Expression and activity of drug targets will be further validated at the protein level in post-mortem spinal cord tissue from ALS patients, to confirm relevance to human disease.

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