Understanding the role of the mineralocorticoid receptor (MR) for regulating the PI3K pathway in female and male hearts.

Summary Class IA PI3Ks are activated by receptor tyrosine kinase receptors and are critical regulators of adaptive heart growth and cardiac protection under stress conditions. Exercise-induced cardiac enlargement provides protection against cardiovascular disease, whereas disease-induced or inappropriate cardiac enlargement leads to heart failure. These distinct forms of growth are associated with different molecular profiles (e.g. mRNAs, non-coding RNAs, and proteins), and targeting differentially regulated genes has therapeutic potential for heart failure. The mineralocorticoid receptor (MR) is a steroid hormone receptor that also has a key role in regulating cardiac function and dysfunction. The MR acts as a transcription factor to regulate gene expression and can also interact with GPCRs (EGFR, VEGFR etc) and their downstream pathways to regulate cell function. This project will investigate if MR-dependent mechanisms of cardiomyocyte function are regulated in mice in which expression of PI3K is reduced, and conversely, whether PI3K pathways are altered in mice lacking the MR In cardiomyocytes. The goal of this project is to determine how the two signalling mechanisms interact in the normal and stressed heart with the view to improve therapeutic outcomes for patients with heart failure. Techniques: RNA isolation, RT and PCR, Immunostaining, Histology, western block, immunostaining/histology, cell culture.