Overview
IMPDH2 is a critical enzyme responsible for the rate limiting step of purine nucleotide biosynthesis. In naïve pluripotent stem cells, it forms large rod-ring structures (RRs) which are hypothesised to control the enzyme’s output when the pool of guanine nucleotides is in high demand. However, whether IMPDH2 interacts with other proteins in these structures is not well defined, and neither is their function during early embryogenesis.
About this opportunity
We want to understand how IMPDH2 RRs form, whether there are other proteins localised to these structures, and whether they are critical for IMPDH2 stability and aggregation.
Objectives: We will take a combined structural bioinformatic and cell biological approach to undertake the following:
- Use computational approaches to predict whether other proteins interact with IMPDH2.
- Generate ESC lines carrying mutations in key IMPDH2 residues that regulate RR formation and assess the consequences of these mutations on potential binding partners
- Determine the functional impact of disrupting IMPDH2’s interaction with binding partners on pluripotency and lineage-specific differentiation.
Experimental Approach: We will apply predictive tools such as AlphaFold 3 to model IMPDH2 interactions in silico, followed by validation using super-resolution microscopy and advanced ESC culture techniques.
Novelty: This project has the potential to understand how IMPDH2 RRs during early mammalian development, providing new insight into how signalling pathways integrate with metabolic and gene-regulatory networks to control pluripotency and differentiation.
Student Development and Training: The student will benefit from co-supervision from the primary and secondary supervisors, gaining training in cutting-edge deep learning-based structural bioinformatics methods, developmental signalling, 3D gastruloid culture, stem cell biology, advanced imaging, and biochemical approaches. Regular supervisory meetings and integration across the two groups will provide robust support, while day-to-day guidance will come from postdocs and peers. Both supervisors have proven records of mentoring early-career researchers and supporting colleagues into diverse scientific and non-scientific career paths. The student will be encouraged to participate in DiMeN training, present at international meetings, and engage with the supervisors’ collaborative networks. This will ensure they develop independence, technical versatility, and a competitive skill set for careers in academia, industry, or translational research.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/