Heart disease causes damaging structural changes, referred to as cardiac fibrosis, that stiffen the heart and weaken its ability to pump blood. Fibrosis disrupts how heart cells function, including how they process genetic information.
We believe certain proteins, called RNA-binding proteins, play a key role in triggering these changes early on. Using advanced stem cell models, we will investigate how these proteins drive cardiac fibrosis and test ways to block their effect.
Target discoveryIn depth
The biomechanical stress associated with pathological heart extracellular matrix (ECM) remodelling modifies the transcriptional and post-transcriptional landscape of cardiac cells. Post-transcriptional events such as alternative splicing (AS), RNA editing, RNA methylation, transport, translation, and degradation facilitate quick adaptation to pathological conditions and are heavily affected in cardiac diseases. RNA binding proteins (RBPs) have been recently shown to contribute to the onset and progression of these pathologies. Our previous work has shown that ECM remodelling in heart disease affects alternative splicing of mRNAs which impacts cardiomyocyte function.
We will use advance protein identification and RNA-seq (mRNA interactome capture (RIC) coupled to TMT Mass Spectrometry or RNA-seq) technologies to identify RBPs that are activated during the early phase of the fibrotic process and assess their potential to induce fibrosis. For this work iPSC-derived cardiac fibroblasts will be used along with in vivo models of myocardial infarction. RBP targets and downstream AS events contributing to ECM remodelling will be identified. We will validate positive RBP targets by inhibition with siRNAs and evaluate the downstream effects by measurement of ECM remodelling.
Partners
This project is supported by:
Professor Sasi Conte, Randall Centre for Cell & Molecular Biophysics, King's College London
Dr Pavel Simara, International Clinical Research Centre of St. Anne's University Hospital, Brno, Czech Republic