About the Cardiovascular Endocrinology laboratory
Heart failure occurs when the heart is unable to pump sufficient blood due to ‘stiffening’ of the myocardium caused by increased tissue fibrosis and changes in myocardial passive stiffness. Tissue injury, with chronic inflammation and fibrogenesis, results in disruption of normal tissue architecture and function and can progress to organ failure. Therapeutic options for chronic fibrosis, in the heart and other organs, are severely limited.
A new biology for the mineralocorticoid receptor (MR)
It was believed that chronic MR activation resulted in high blood pressure only, and increased Angiotensin II signalling caused fibrosis. However, we have shown that mineralocorticoids cause cardiac fibrosis via direct actions in the heart, contributing to large-scale clinical trials that established a major role for MR signalling in heart failure.
The 'textbook' model of MR biology is flawed
The MR controls numerous processes in non-renal tissues. Understanding MR mechanisms of action in these tissues is a prerequisite for future discovery of drugs that are selective for MR in the heart. Accordingly, we have developed a suite of tissue-specific MR null mice and genetically modified cell lines in order to understand this new MR biology as it relates to heart disease. Outcomes of this laboratories work identifying cell selective pathways, conformational changes and ligand dependent protein interactions for the MR have led to engagement with industry and together with clinical testing of preclinical data have created a pipeline for translating new therapies for cardiac fibrosis and heart failure.
Ongoing projects seek to identify novel mechanisms of MR signalling in macrophages and cardiomyocytes to generate new directions for the development of a selective MRA for cardiac fibrosis.
- Identify MR dependent mechanisms in tissue macrophages that regulate inflammatory and fibrotic pathways and determine the function of novel MRA signalling in vivo in clinical studies.
- Define MR and molecular clock interactions to provide new knowledge for MR actions in cardiomyocytes (i.e. disruption of the molecular clock as a driver for cardiac fibrosis).
- Engineer and test novel MR modulating compounds for cardiac fibrosis and inflammation that may also have fewer side effects.