Tapton School sixth form students have been carrying out scientific research in the school laboratories since 2012. Their aim is to use the zebrafish model organism to identify novel molecular and genetic mechanisms in cardiovascular disease.
This research is performed with the support from the laboratory of Dr Tim Chico in the Bateson Centre, Department of Biomedical Science at the University of Sheffield, and funded by the Wellcome Trust Authentic Biology Project.
Cardiovascular disease (CVD) is the single largest cause of death in the UK. It accounts for around 200,000 deaths a year, mostly as a result of heart attack or stroke. Arterial blockage (or occlusion) is a major factor in CVD. Blockage may occur when a blood clot obstructs the flow of blood in an artery.
We aim to characterise novel genes that are differentially expressed in a clinical analysis of patients who have suffered a heart attack by studying orthologous genes in the Zebrafish cardiovascular system. These genes may be important in the response to a heart attack or act as biological markers for heart disease. We analysed a list of 82 genes and selected ALAD, CDKL1, FECH, and TBC1D19 for further study. Preliminary data for Cyclin-Dependent Kinase-Like 1 (CDKL1) show that in 24-48hpf embryos it is localised to the hypochord, a precursor to the dorsal aorta. Its expression pattern changes in a model of hypoxia, in which blood vessel formation is stimulated. These results suggest that CDKL-1 may mediate signalling for blood vessel formation, which is essential for recovery following cardiovascular failure.
The cyclin dependent protein kinase family regulates a wide range of cellular functions such as cell cycle progression, differentiation, and apoptosis. They are kinase enzymes which regulate other proteins by attaching a phosphate to serine or threonine amino acid residues in target proteins. They have two functional domains, a cyclin binding domain and a kinase domain. Cyclin binding activates these proteins mediating a cellular process via a signalling cascade. CDKL1 has been classed as cyclin dependent “like” as it contains the conserved domain for binding cyclin “KKIARLE” as well as a kinase domain. The structure of the kinase domain has been determined and is very similar to the well characterised human CDK2 (1,2). No function has been assigned to CDKL1. Our study identified an elevated expression in response to heart attack and In Situ hybridisation analysis of Zebrafish indicates that CDKL1 may signal blood vessel formation. Through Genome Expression Omnibus searches we propose that CDKL1 mediates this through the Sonic Hedgehog, VEGF, NOTCH signalling pathway.