Developing new treatments for cardiovascular disease and sudden cardiac death by coupling stem cells with Cas9/CRISPR gene editing

Mutations that disturb structure or function of heart cells (cardiomyocytes) can lead to sudden cardiac death, which remains as one of the most common causes of reduced lifespan in otherwise healthy under 35 year olds. While treatments for some conditions have improved, understanding of many could be improved if additional tools & platforms were available to understand the underlying molecular mechanisms involved. Ultimately, such platforms could be used to evaluate novel gene- and drug-based therapies. To this end, we have been combining human induced pluripotent stem cell (hiPSC) systems with state-of-the-art gene editing using Cas9/CRISPR to produce cardiomyocytes that do or do not carry potentially dangerous mutations, including those underlying hypertrophic cardiomyopathy. By collaborating with international colleagues in Spain and Germany, and by using our large £2m robotic and phenotypic suite, we have shown in both 2D and 3D systems that key aspects of patient pathophysiology are recreated in these ‘disease in a dish’ models. This includes altered beating (arrhythmias), calcium handling, metabolism and force generation. We want to continue these analyses and extend them to other disease states, as well as evaluate whether different drugs can be used to treat these conditions. Therefore, the project will require a talented, committed and highly motivated student who has skills, or is willing to learn them, in some or all of the following approaches: hiPSC culture and differentiation to cardiomyocytes; Cas9/CRISPR gene editing; RNAseq / transcriptomics & bioinformatics; cell phenotyping; robotics; pharmacology. The student should also be willing to travel to collaborators labs, as required.

A useful review article in this area is Denning et al., Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform. Biochim Biophys Acta. 2016 Jul;1863(7 Pt B):1728-48. doi: 10.1016/j.bbamcr.2015.10.014.