Regulating the receptors: new targets for fine-tuning hormone receptor actions in health and disease

Steroid hormone receptors (nuclear receptors) are expressed in many tissues and act as transcription factors to control cellular and tissue function. Co-regulatory proteins modulate these receptors and are expression in a tissue, disease and temporal specific manner. The coregulators therefore allow the nuclear receptors to have selective actions. Co-regulators can have profound effects on receptor activity and may be targeted therapeutically for the treatment of a range of diseases. We identified novel mineralocorticoid receptor (MR) co-regulators from the heart and kidney that may be important for cardiovascular health and disease pathways. This project will evaluate how MR coregulatory proteins control the MR in a tissue and cell selective manner using a range of molecular techniques (RTPCR, CoIP, transactivation assays) and using immunostaining of heart and kidney of archival tissues. This project will demonstrate how the MR regulates tissue gene transcription and function across 2 tissue in which the MR plays a critical role. Moreover, this project will extend to testing how novel coregulators influence MR regulation by current and novel antagonists developed for use in cardiovascular disease. Outcomes of this project will be to provide novel functional data for MR action across different tissues, development of new cell based tools to screen drugs in development for cardiovascular disease and an understanding of how tissue injury disrupts normal regulation of the receptor.