Mutations in nuclear envelope proteins and nuclear lamina cause inherited heart disease. One of the most frequent observations in patients with nuclear envelope mutations are lethal arrhythmias that are associated with alterations in the cardiac conduction system. However, the underlying mechanisms remain obscure.
Excitingly, we have preliminary data suggesting that LEM domain proteins play an essential role in the formation of critical components of the conduction system. The conduction system is derived during heart development from various cell types that importantly include epicardial cells.
This project will target LEM domain proteins using siRNA-mediated knockdown in primary murine epicardium undergoing epithelial-to-mesenchymal transition (EMT) and human embryonic stem cells to characterise the functional effects of removing LEM domain proteins on cell proliferation, death, migration, and differentiation. Following which, epicardium-specific knockout mice will be generated to ablate LEM domain expression using floxed mice to complement the in vitro approaches.