Despite current treatments, the prognosis of heart failure is poor: approximately 50% of patients die within 5 years of diagnosis. Adult human hearts cannot produce new cardiomyocytes (i.e. heart muscle cells) to replace those that die upon injury, such as a myocardial infarction, leading to maladaptation of the remaining ventricular tissue (pathological remodelling) and eventually to heart failure.
Therapies that would promote regeneration of the injured myocardium would revolutionize the treatment of ischemic heart disease and heart failure. Remarkably, zebrafish and neonatal rodents can regenerate their hearts after an injury through revascularization of the injured area by angiogenesis (i.e. proliferation and migration of vascular endothelial cells) and renewal of the injured heart muscle by proliferation of cardiomyocytes. While zebrafish retain this capacity throughout their life, rodents can only regenerate injured myocardium during the first couple of days after birth. Clinical evidence also suggests that the human heart has some regenerative capacity at the time of birth. The exact mechanisms of cardiac regeneration and the postnatal loss of regenerative capacity of the heart are however unknown.
Our research aims at identifying novel drug targets by elucidating the mechanisms that regulate cardiac regeneration and the postnatal loss of regenerative capacity. One of our main interests is metabolic regulation of cardiac regeneration: We have identified a number of metabolic pathways that are temporally regulated in the heart over the early postnatal period when the regenerative capacity is lost and may thus play a role in regenerative processes. The central cell types we are interested in are cardiomyocytes and vascular endothelial cells.
Pathological remodelling of the left ventricle refers to thickening (hypertrophy) and stiffening (fibrosis) of the ventricular wall in response to increased strain on the heart. It causes progressive deterioration of cardiac function and can eventually lead to heart failure. Current treatments are not effective enough to completely stop or reverse the progression of ventricular remodelling, and new therapies are thus urgently needed. By investigating the signalling mechanisms of hypertrophy and fibrosis, we aim to find new ways to treat left ventricular hypertrophy and cardiac fibrosis.
Another main aim of our research is the discovery of new compounds with regeneration-promoting activity. We screen and characterise new compounds designed and synthesized together with the medicinal chemistry group led by Prof Jari Yli-Kauhaluoma. The close collaboration is essential for both developing new, pharmacologically active compounds and for deciphering their mechanisms of action. We use both target-based and phenotypic screening, and select the most promising hit compounds for further pharmacological and toxicological characterisation as well as for molecular modification to improve the properties of the compounds.
For drug target identification as well as compound screening and characterisation, we utilise a number of modern techniques including human pluripotent stem cell (hPSC)-derived cardiomyocytes and endothelial cell, high content imaging and analysis (HCA), and multiple levels of omics analyses (transcriptomics, proteomics and metabolomics). In addition, we collaborate on developing new microfluidistic cell culture platforms, nanoparticle-based targeted drug delivery to the heart, and mass spectrometry-based analytical techniques.