Violetta Steeples

My research utilises induced pluripotent stem cells (iPSCs) to model inherited cardiomyopathies. Cardiomyopathies are diseases of the heart muscle which affect its structure or function. They often present in adolescence or early adulthood with symptoms that may include chest pain, palpitations, shortness of breath, exercise intolerance and, in some cases, sudden death. Inherited cardiomyopathies can be associated with a mutation in any of number of genes, including genes encoding proteins with a structural role in the sarcomere (the contractile unit of heart muscle cells) and energy metabolism, as well as in genes with, as yet, not fully defined functions. iPSCs have the ability to divide indefinitely to make more stem cells or can be differentiated to generate any specific cell type. I use genome-editing to precisely introduce the mutations found in inherited cardiomyopathies into the DNA (the molecule containing the cell’s genetic code) of iPSCs. In my research, I use small molecules to direct differentiation of iPSCs with or without cardiomyopathy-associated mutations into heart muscle cells (cardiomyocytes) which beat spontaneously in culture. I then use these cardiomyocytes to gain insight into the physiological (e.g. beating strength and frequency) and biochemical (e.g. RNA and protein expression) differences associated with cardiomyopathy mutations. My current research uses adenovirally encoded fluorescent molecules to investigate how myosin binding protein C mutations, found in hypertrophic cardiomyopathy patients, alter contraction, calcium handling and metabolism in iPSC-derived cardiomyocytes.

I have a background in cardiac research having worked as a research assistant and subsequently DPhil student in the laboratory of Professor Houman Ashrafian and Professor Hugh Watkins in the Division of Cardiovascular Medicine. As a research assistant I had the opportunity to work on a number projects in fields ranging from vascular biology to cancer research, whilst my DPhil focused on the role of intermediary metabolism in heart failure. After my DPhil I moved into the field of haematology, working as a research assistant in the Nuffield Division of Clinical Laboratory Science. I investigated differential mRNA splicing in myelodysplastic syndromes, working with a range of cell types including haematopoietic stem and progenitor cells. I returned to the Division of Cardiovascular Medicine working with Dr Katja Gehmlich in a position which brought together my background in cardiovascular research with the culture of stem cells. In my current position with Dr Chris Toepfer and Prof Hugh Watkins I continue to work with iPSC-derived models of cardiomyopathy.