Decoding the process of fibrosis to identify new therapeutic targets for heart failure

2020 Vanguard Grant

Years funded: 2021-2022

A startling one in three deaths in Australia are due to cardiovascular disease (CVD). Notwithstanding the considerable improvements, CVD is still associated with a substantial clinical burden and represents Australia’s largest direct health care cost. In particular, heart failure has become a major issue. Approximately 50% of heart failure patients relapse within one year of diagnosis and only half of patients survive beyond 5 years. Cardiac fibrosis causes adverse tissue remodelling that is a hallmark of heart failure pathophysiology. However, despite its prevalence, there are fundamental gaps in our understanding of cardiac fibrosis, and there are no effective therapies to inhibit or reverse fibrosis in the heart. This highlights crucial need for new and innovative therapies to prevent cardiac fibrosis in heart failure patients.

Medicines targeting a large family of proteins, G protein-coupled receptor (GPCRs), are important frontline therapies for the treatment of CVD and heart failure. Nevertheless, these therapies are only directed towards a small fraction of cardiac GPCR repertoire, with many remaining receptors that could be new cardiovascular therapeutic targets. We have previously established that the adenosine A2B receptor (A2BR) has an important role in fibrotic tissue remodelling and has beneficial anti-fibrotic effects following a heart attack. In addition, in work recently published in the prestigious journal Cell, we have recently identified a new activator for another receptor (GPR161) that could be involved in cardiac fibrosis.

In this project, we focus on A2BR and GPR161 as model receptors to understand the detailed molecular mechanisms that are involved in fibrosis. These experiments span cell-based studies to a pre-clinical model of human heart tissue, and will address our hypothesis that there is convergence in GPCR-mediated signalling in fibrosis. We anticipate that our research will identify potential targets for the treatment of fibrosis.