Characterising congenital heart disease variants in Drosophila

Congenital heart disease (CHD) is the most common congenital defect affecting approximately 1% of live births contributing to a significance incidence of birth-defect related mortality. CHD includes a wide range of cardiovascular phenotypes spanning localized anatomical defects to more complex abnormalities with common forms including bicuspid aortic valve (BAV) and Tetralogy of Fallot (TOF).

A significant underlying cause of CHD is genetic. Although many of the genetic variants identified disrupt genes that play a role in normal cardiac development the mechanisms are not fully understood. In addition, large scale whole exome sequencing studies are identifying increasing numbers of rare variants in these genes, however translating the position and nature of these rare variants into new biological understanding remains a challenge with a heavy reliance on relatively slow mammalian studies in which variants are studied one by one.

The goal of this studentship proposal is to develop a novel Drosophila model to accelerate the translation of genetic findings to a new mechanistic understanding of CHD and to speed up the initial screening of variants for further study. We will use the Notch pathway because of the highly conserved nature of the pathway and the large number of CHD associated rare variants identified.

 Training and environment

This studentship focuses on the cell biology of heart development in the context of human disease and invertebrate embryology. The supervisors are experts in Drosophila, chick, mouse and human heart development and the student will gain experience and exposure to be able to connect their work to these other model systems. The student will receive training in fundamental anatomy techniques, including tissue fixation, immunostaining, microscopy and 3D reconstruction, that will allow them to start a career in the anatomical sciences. The student will also have excellent opportunities to hone their teaching skills with a wide variety of modules available within the School that require practical demonstrators.