Coronary heart disease (CHD) leading to myocardial ischaemia is the predominant cause of heart failure (HF) and premature mortality in the UK. CHD occurs when the blood vessels of the heart (coronary arteries) become narrowed by fatty material (atheroma) and reduce blood flow to heart muscle (myocardial ischaemia). If the coronary artery is occluded then an area of lethal tissue injury in heart muscle called a myocardial infarction (MI) can be produced. The subsequent structural and functional changes in the surviving heart muscle can lead to poor cardiac pump function and HF. Novel therapeutic strategies to preserve cardiac pump function are urgently needed to treat patients with myocardial infarction and thereby improve patient survival rates and quality of life.
The Runx family of genes (Runx1,2&3) encode for DNA binding transcription factors (Runx1,2&3) which regulate gene expression. Recently, increased Runx1 expression has been demonstrated in the hearts of patients with MI. In line with these data, our recent work demonstrates increased Runx1 expression in a mouse model of MI. However, despite these observations, the role Runx1 plays in heart function remains unknown. We have made a novel and exciting discovery that higher Runx1 expression levels correlate with poor cardiac pump function. In order to corroborate this finding, we have produced a heart-specific knockout of Runx1. When MI is induced in this transgenic model, cardiac pump function is markedly improved suggesting that reducing Runx1 expression in the heart is a novel therapeutic approach to limit the progression of cardiac dysfunction in patients with MI.
This studentship will investigate the relationship between Runx1 expression in the heart and the development of heart failure. In addition, the project will develop therapeutic strategies to reduce Runx1 expression in cardiac disease in order to prevent progression to heart failure.
The project will enable the student to be trained in in vivo rodent models of heart disease, integrative physiology, molecular biology and gene therapy approaches.