Heart failure (HF) is one of the leading causes of death globally, with just under 1 million people affected in the UK. HF occurs when the heart cannot pump blood effectively to meet the body’s demands. There is currently no cure—available treatments mainly help control symptoms and slow the disease. We are working to find new and effective ways to treat HF, and we need your help. Specifically, you will be exploring the hypothesis that the metabolic enzyme isocitrate dehydrogenase (NADP(+))1 (IDH1) contributes to the development of HF. We identified IDH1 as a potential therapeutic target through a screen in UK Biobank participants, predicting metabolic gene expression and its association with HF. Analysis of public datasets confirmed that IDH1 expression is downregulated in failing hearts. IDH1 catalyses the conversion of isocitrate to alpha-ketoglutarate and CO2, while reducing NADP+ to NADPH, and it can influence cellular processes like mitochondrial ATP production, glutamine metabolism, and epigenetic regulation.
The objective of this project is to investigate the role of IDH1 in new human in vitro models to study heart disease, with a specific focus on IDH1 role in modulating the metabolic and epigenetic changes occurring during HF.
The overarching objectives are to a) establish IDH1 loss-of-function and gain-of-function systems in human models of pathological cardiac remodelling (Year 1); b) Identify the functional consequences of IDH1 manipulation during cardiac pathological stress (Year 2); c) study the IDH1-mediated changes in metabolomics and epigenetic during stress conditions to identify novel potential therapeutic targets to treat HF (Year 3-4).
Techniques and skills: You will learn cutting edge techniques including differentiation of human induced pluripotent stem cells (iPSC) into cardiomyocytes (hiPSC-CM), generation of human engineered heart tissues (EHT), state-of-the-art metabolomics and stable isotope-resolved flux analysis, extracellular flux analysis, nanopore sequencing for epigenetic profiling, FACS, immunofluorescence, molecular biology, confocal imaging, western blotting, qPCR and data analysis. All of these are already established in your supervisors’ laboratories.
3-months rotation project: Learn to differentiate iPSC into cardiomyocytes and perform initial loss-of-function experiments.
Year 1-2: Development of a human heart failure model using hiPSC-CM and EHT; construction and validation of gene modulation tools, analysis of IDH1 manipulation effects on hypertrophic remodelling, contractile force, mitochondrial function, and gene/protein expression.
Years 3–4: Metabolic and epigenetic profiling of hiPSC-CM and EHT after IDH1 manipulation; data analysis, target identification and validation.
Year 4: Final data analysis, thesis writing, conference presentations, and manuscript submissions.
