Heart regeneration & development
Research in our laboratory, which is based in the Sherrington Building, focuses on two projects.
Heart regeneration in Mexican cavefish and zebrafish
After a heart attack, the infarcted heart muscle dies and is replaced by non-contractile scar tissue in those fortunate enough to survive the heart attack. This non-contractile fibrous scar tissue will never be replaced by heart muscle and may cause severe contractile dysfunction, resulting in chronic heart failure. While the human heart has no inherent ability to regenerate cardiac muscle after a heart attack, by contrast, certain fish efficiently regenerate lost cardiac muscle. Removal of up to 20% of the ventricle of, for example, the zebrafish heart, results in the wound tissue being replaced with new, functional cardiac muscle. Understanding the mechanisms by which natural heart regeneration occurs in fish will provide insights into regenerative failure in humans and the possible therapies.
We use both zebrafish and Mexican cavefish, Astyanax mexicanus, to research heart regeneration. The zebrafish is a well-established, easily genetically modifiable model for understanding how natural heart regeneration occurs. Like zebrafish, the teleost fish Astyanax mexicanus can regenerate its heart after injury. Astyanax mexicanus is a close relative to the zebrafish and a single species, which comprises eyed surface- and eyeless cavefish populations. The two populations arose around 1.5 million years ago, when the surface fish diverged into distinct cavefish populations in the north of Mexico. The cave-dwelling populations have since evolved independently with eye and pigment degeneration, redundant characteristics in the absence of light. Instead, they developed highly sensitive taste buds. We use several approaches unique to either zebrafish or cavefish to identify new genes and importantly to uncover novel basic mechanisms involved in vertebrate heart regeneration with the aim to help identify strategies to restore the functional cardiac muscle after a heart attack in human patients.
Slit-Robo signalling during mammalian heart development and disease
The second research project focuses on the roles of the Slit-Robo signalling pathway during mammalian heart development and disease. The Roundabout (Robo) transmembrane receptors and their Slit ligands became well-known for their chemo-active role in axonal guidance in the embryonic nervous system, however, knowledge on their involvement during heart development is very limited. We have shown that disruption of the Slit-Robo signalling pathway results in congenital heart defects, such as ventricular septal defects, valve malformations and pericardial defects. We are now using conditional knock-out approaches and functional analysis to identify how this signalling pathway controls many different aspects of heart development and disease.