Project ID CM-HD2024_40


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Cardiac themeWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Department of Cardiovascular ImagingWebsite

Exploring the role of LEM domain proteins in cardiac conduction and inherited cardiomyopathy

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.

Representative Publications

  • Lem2 is essential for cardiac development by maintaining nuclear integrity. Ross JA…Stroud MJ$. 2023, Cardiovasc Research. doi: 10.1093/cvr/cvad061
  • Myonuclear alterations associated with exercise are independent of age in humans. Battey E…Stroud MJ$. 2023. J Physiol. doi: 10.1113/JP284128
  • Nesprin 1alpha2 is essential for mouse postnatal viability and nuclear positioning in skeletal muscle. Stroud MJ* et al. 2017 J Cell Biol doi: 10.1083/jcb.201612128
  • Cardiac lymphatics are heterogeneous in origin and respond to injury. Klotz, L.*, Norman, S*., Vieira, J. M*., et al. 2015 Nature. doi: 10.1038/nature14483
  • BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease. Vieira JM et al. 2017 Nature Communications. doi: 10.1038/ncomms16034