Understanding regulation of inflammatory signalling by the mineralocorticoid receptor

Background: Heart failure, diabetes and chronic kidney disease affect millions of people worldwide and are characterised by persistent inflammation and progressive tissue fibrosis. The mineralocorticoid receptor (MR) is a key driver of these processes and is already an important therapeutic target in cardiovascular medicine. Current MR antagonists improve survival in heart failure, yet their use is limited by adverse renal effects, including hyperkalaemia, because they block both pathological and essential physiological MR functions. Recent work from our laboratory has demonstrated that MR signalling in macrophages regulates inflammatory activation, metabolism and tissue remodelling independently of its classical actions in the kidney. We have also discovered that MR activity is controlled by a complex network of interacting proteins, signalling pathways and metabolic regulators that differ between tissues and disease states. The molecular mechanisms that drive inflammatory MR signalling in human immune cells remain poorly understood. Understanding these pathways is essential if we are to develop safer therapies that selectively target disease-causing MR activity. Hypothesis: We hypothesise that pathological MR signalling in macrophages is mediated by specific protein interaction networks and metabolic pathways that are distinct from those regulating normal physiological MR function. These disease-associated signalling networks may serve as new therapeutic targets with better safety profiles. Project Goals: This project will combine human primary macrophage models, proteomics, phosphoproteomics and metabolomics to define the signalling pathways that drive pathological MR activation. Students will investigate how MR regulates inflammatory activation, cytokine production and cellular metabolism and determine whether these pathways are altered in patients with cardiometabolic disease. The project will also integrate emerging proteomic datasets to identify novel MR interacting proteins and signalling nodes. Potential Outcomes: This work will generate fundamental new knowledge about human inflammatory signalling and may identify novel biomarkers and therapeutic targets for heart failure, diabetes and fibrotic disease. Students will gain training in advanced molecular biology, systems biology and translational cardiovascular research while contributing to the development of next-generation precision therapies.