Heart muscle cells interact with their surrounding extracellular matrix. The composition and physical properties of the extracellular matrix can either promote or inhibit the growth of new heart muscle cells following a heart attack.
This project seeks to use advanced therapeutic technologies to modulate the extracellular matrix and create conditions that promote the growth of new heart muscle cells.
Target discoveryIn depth
After myocardial infarction (MI), neonatal mice heal through a process of regeneration. An intermediate step is the formation of a collagen-rich but fully resorbable 'patch'. This is distinct from the permanent scar which is made by the adult mouse and humans after MI.
Using single-cell RNA sequencing in postnatal day 1 (P1) versus P7 mice, we have identified high levels of expression of certain classes of protease inhibitor. Our working hypothesis is that this class of molecules prevents a post-translational modification of collagen which, in turn, inhibits the crosslinking of collagen fibrils, thus resulting in a provisional lattice-like patch, not a highly organised collagen scar.
We are working to develop modalities for delivery of therapeutic peptidase inhibition that will allow for appropriate temporal and spatial expression within the adult post-MI heart, recreating optimal conditions for regeneration. We are harnessing the normal cellular response to injury to support delivery of the therapeutic molecules. We will evaluate the expression and tissue distribution of these molecules, as well as the response of the myocardium in terms of the consequent matrix composition and fibre orientation in usual conditions and post-MI.
These studies will lead to therapeutic approaches that recreate neonatal conditions in injured hearts to promote repair.