Regulating macrophages in heart disease - targeting new hormone receptor pathways

The mineralocorticoid receptor (MR) is an established therapeutic target for heart disease. However current drugs are not selective for the heart and disease pathways and cause side effects by blocking the receptor in other tissues where the MR regulates physiological sodium, potassium and fluid balance and thus blood pressure control. Work from this lab has shown the MR also regulates non-epithelial cell types including inflammatory cells such as macrophages. In animal models, cardiac fibrosis is caused by mineralocorticoid/salt administration and attenuated by MR blockade or gene knockout (deletion) of the MR In macrophages. The recent identification of the cardio-protective effects of macrophage-specific deletion of the MR is an exciting advance in our understanding of disease processes and highlights new therapeutic targets that could lead to new treatments for the treatment of cardiac failure and hypertension that are specifically designed for macrophages. In these cells, the actions of the MR are not completely characterised but in many cases do not relate to salt or fluid regulation. At present, the cascade of events leading to MR activation and how MR activation results in inflammation and fibrosis are not clearly defined. The goal of this project is to identify novel pathways using proteomic and genomic screening technologies and to define and characterise these pathways. This study will use animal tissue samples from male and female mice subjected to models of heart disease, clinical samples (where possible) and cell lines to identify novel pathways regulating MR actions. This will include investigating tissues other than the heart in some cases, i.e. liver and kidney. If time permits, bioinformatic analyses of large clinical databases will be involved. In this way, we hope to identify and characterise novel mechanisms of heart disease, determine the optimal way to treat patients and avoid the serious side effects of current treatments. Techniques involved: tissue culture, cytokine assays, RTPCR, western blot, bioinformatics, FACS