Temporal control of the mineralocorticoid hormone receptor - new mechanisms in the pathogenesis of heart disease.

The mineralocorticoid receptor (MR) is a ligand activated transcription factor that is important for physiological control of blood pressure and water homeostasis in epithelial cells. In these cells MR is controlled by a mineralocorticoid hormone, aldosterone. However, the MR is expressed in many other cell types where cortisol, not aldo, is the main ligand for the receptor. In these ‘non-epithelial’ cells the biological function of the “cortisol-bound” MR (cort-MR) is largely unknown. Preliminary data show the molecular clock is a novel and important target of the MR in the heart1. It has been shown that in cardiac cells: (i) cort-MR and aldosterone-bound MR (aldo-MR) have distinct but overlapping patterns of transcription of molecular clock genes, (ii) molecular clock components reciprocally regulate MR transcriptional responses, and (iii) in vivo, MR activation is dependent on the time of day. The original observations for a link between the MR and the molecular clock were made using transgenic animal models of heart disease; however, these highly novel data generated exciting novel insights for MR regulation of molecular clock and suggest a plausible and fundamental biology for cort-MR in peripheral tissues. The connection between the MR and the molecular clock is not clear. The goal is to understand how modern environmental circadian disruptors interfere with the body’s normal response to steroid hormones. Our goal is to identify novel therapeutic targets and/or early biomarkers of cardiovascular disease risk that are are associated with pathogenic MR activation. Understanding how the molecular circadian clock and the MR interact may lead to chronotherapeutic approaches for cardiovascular disease therapies. Techniques will include immunohistochemistry, cell culture, western blotting and RT-PCR techniques and potentially preclinical animal models.