Project supervisor: Dr Karl Herbert, Depart of Cardiovascular Sciences
Industrial collaborator: Dr Amy Pointon, AstraZeneca.
University of registration: University of Leicester
Project title: Macrophages and Maintenance of Cardiac Myocyte Homeostasis
Macrophages resident within the atrioventricular node maintain homeostasis through electrical coupling with myocytes to effect normal cardiac conduction but also secrete paracrine immune mediators to modulate cardiac function and morphology. Roles for cardiac macrophages in ageing and mechanisms of cardiotoxicity are emerging. The majority of compounds that cause pathological adverse events in the heart interact with mitochondria. Our recent data suggest that macrophage activation, by mitochondrial perturbation, is due to redox signalling events arising within this organelle. The current collaboration aims to further our understanding of biological mechanisms whereby xenobiotics modulate normal macrophage function which in turn impacts upon cardiac myocyte biology through cell-to-cell and paracrine signalling; development of new mechanistically-relevant in vitro models will support early assessment of compound safety. A novel in vitro model incorporating macrophages within an established AstraZeneca, human 3D cardiac myocyte culture will be developed.
Alongside macrophage-myocyte co-cultures and transfer of macrophage secretome to cardiac myocytes, this model will be used to investigate the influence of macrophage inflammasome activation on healthy myocyte function. Chemical compounds and genetic manipulations which modulate mitochondrial function will be used to investigate the role of mitochondrial signals in generation of inflammasome activation and the effect of macrophage-derived signals on maintenance of critical functions of the cardiac myocyte. The planned programme of work is aimed at understanding basic physiological mechanisms of heart cells. By focussing on mechanistically-relevant in vitro assessments that better reflect adverse effects on the heart in vivo, the work addresses safety and efficiency within the early drug development pipeline. Whilst working towards reduction of drug failure rates to reduce costs to the pharmaceutical industry and ultimately to customers, such as the NHS, the work supports the reduction and replacement of animals in research. Moreover, since we know that heart biology is modified with age and as we recognise changes in macrophage numbers and biological function with age in man, this work has implications for healthy cardiac ageing and its consequences.
Contact: Dr Karl Herbert, University of Leicester