Exploring metalloprotease and extracellular matrix dynamics in cardiac fibrosis

Cardiac fibrosis is often defined as the excessive production of extracellular matrix (ECM) proteins, which negatively impact the ability of the heart to contract and relax. Alongside production, the ECM undergoes extensive remodelling facilitated by metalloproteases and other ECM modifying enzymes, leading to changes to matrix crosslinking, structure and ultimately quality. Using human cardiac organoids – a live contracting 3D model incorporating many important heart cell types – we have established a model for cardiac fibrosis to monitor these changes. We have also discovered that different pro-fibrotic drivers will elicit divergent changes in ECM components and contractile outcomes. These findings suggest that ECM quality may be governing irregular contraction rather than matrix protein quantity.

This project aims to investigate the nuances of ECM production and degradation during cardiac fibrosis-related tissue remodelling.

The first part of this project involves bioinformatics analysis on the extensive RNA sequencing datasets already generated in the lab and through publicly available sources. We will use these data to define enzyme expression changes during the development of cardiac fibrosis. Depending on the duration of the project, these regulatory targets will be experimentally modulated using human cardiac organoids followed by functional analysis, mass spectrometry-based proteomics and advanced microscopy techniques to monitor ECM remodelling. As an extension of this work, we may have the opportunity to cross-validate these organoid studies with fibrotic human and/or mouse heart proteomics.

This project will improve our understanding of the fundamental mechanisms that are regulating ECM during the development of cardiac fibrosis, which may pave the way for future anti-fibrotic treatment strategies.