Tissue select regulation of the mineralocorticoid receptor for developing heart failure therapies.

Background: Current MR antagonists are among the most effective therapies for heart failure, yet their use remains constrained by adverse renal effects. Our laboratory and collaborators are working to developed novel approaches to selectively modulate MR activity by targeting receptor-coregulator interactions and targeting tissue-specific signalling pathways. These data provide a foundation for a new generation of precision therapeutics designed to preserve cardiovascular benefits while minimising renal side effects. The mechanisms that distinguish beneficial from harmful MR activation remain incompletely understood, and no currently available therapy selectively targets pathological MR activation. Hypothesis: We hypothesise that selective modulation of MR signalling can uncouple cardiovascular protection from renal side effects and that novel compounds targeting MR-coregulator interfaces will provide safer and more effective therapies. Project Goals: Students will participate in an early-stage discovery program involving molecular pharmacology, computational modelling, medicinal chemistry and translational physiology. Projects may include characterising MR-coregulator interactions, evaluating tissue-selective signalling pathways and testing candidate therapeutics in preclinical disease models. Potential Outcomes: This project offers an opportunity to participate in a discovery-to-translation pipeline. Students will receive training including molecular pharmacology, drug development and translational cardiovascular science.