Toepfer Group: Metabolic Reprogramming in Hypertrophic Cardiomyopathy: Integrating Patient-Derived iPSC and Organoid Models with In Vivo Cardiac Energetics and Oxygen Sensitive Cardiac Magnetic Resonance Imaging

About the Research 

Our lab investigates the pathophysiology of inherited cardiomyopathies by combining advanced imaging, stem cell modelling, and data science to unravel genotype-phenotype relationships and uncover novel therapeutic targets. A growing body of evidence highlights energy depletion as a central feature of hypertrophic cardiomyopathy (HCM), yet the specific impact of different sarcomeric variants on cellular metabolism remains poorly understood. Direct access to myocardial tissue is limited, prompting the need for human-relevant, scalable models of disease.

This project will focus on uncovering variant-specific metabolic signatures in HCM using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from well-characterised, genotyped patients who have undergone deep metabolic and functional phenotyping using advanced 31P-MRS and oxygen-sensitive cardiac MRI.

Building on our prior work, which established CRISPR-engineered iPSC-CMs that mimic metabolic deficits seen in primary cardiomyocytes, the student will: a) Derive and culture iPSC-CMs from patients with specific HCM-causing sarcomeric mutations; b) Develop 3D cell culture techniques to generate self organising cardiac organoids; b) Perform in-depth metabolic phenotyping using proteomics, oxygen consumption assays, and glycolytic flux measurements c) Integrate computational modelling to infer pathway-level disruptions and energetic imbalance d) Correlate in vitro findings with non-invasive imaging biomarkers of energetics and disease severity e) Investigate the therapeutic potential of metabolic modifiers/novel treatments in rescuing energetic derangement in selected lines f) Stem cell biology, cardiomyocyte differentiation, and tissue culture; g) spatial trancriptomics of organoids; h) Mass spectrometry-based proteomics and bioinformatics,i) Seahorse XF metabolic flux analysis and related functional assays, j) Computational systems biology and network modelling, k) Correlative analyses between in vitro and in vivo human imaging data.

This project sits at the interface of cardiology, molecular biology, and translational imaging science, with the potential to identify precision metabolic therapies for distinct HCM genotypes and to inform future clinical trial stratification. It also contributes to the development of a living iPSC biobank from patients with defined cardiac phenotypes, supporting future discovery and grant applications. This project is ideal for candidates from biomedical sciences, molecular biology, or physiology backgrounds, particularly those with an interest in cardiovascular disease, metabolism, and translational stem cell research. Prior wet lab experience is advantageous but not essential.

This MSc by Research project is suitable for part-time research.

Training Opportunities 

1. Learn to reprogram patient PBMCs and differentiate iPSCs into cardiomyocytes.
2. Gain experience in editing sarcomeric mutations in iPSCs for disease modelling.
3. Assess contractility, calcium handling, and beat rate in iPSC-CMs.
4. Acquire skills in 3D cell culture techniques to generate self-organising cardiac organoids & tissue engineering
5. Measure oxygen consumption, ATP production, and glycolytic function in real time.
6. Perform mass spectrometry-based proteomic profiling and pathway analysis.
7. Use systems biology tools to model disrupted energetic pathways.
8. Correlate cellular metabolic findings with in vivo CMR and 31P-MRS metrics.
9. Combine omics data with imaging phenotypes to discover genotype-specific signatures.
10. Contribute to a living iPSC biobank for future metabolic and therapeutic screening.
11. Test candidate compounds to rescue metabolic defects in variant-specific models.
12. Use immunofluorescence, live-cell imaging, and mitochondrial function assays.
13. Learn transcriptomic/proteomic analysis tools (e.g., Ingenuity, GSEA, Cytoscape).
14. Training in contamination control, mycoplasma testing, and differentiation quality metrics.
15. Present findings in lab meetings and conferences; contribute to manuscripts and grant applications.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Additional Supervisors 

1. Betty Raman

Publications