Development and Validation of a REV-ERBalpha HTS Assay

Burris, Thomas

Abstract

The human nuclear hormone receptor (NHR) super family consists of 48 members, approximately half of which have no identified ligands and are termed """"""""orphan receptors"""""""". Nearly all of the NHRs with identified ligands have been successful targets for drugs treating a variety of diseases including diabetes, dyslipidemia, inflammation, and cancer. REV-ERB1 and REV-ERB1 were originally identified as orphan members of the NHR super family and play critical roles in control of lipid and glucose metabolism and the circadian rhythm. We recently discovered that REV-ERBs are indeed ligand-regulated and that the porphyrin, heme, behaves as an agonist binding directly to the receptors and altering their transcriptional activities. Beyond the natural ligand, heme, there are no validated synthetic ligands to use as probes to characterize the biological roles of the REV- ERBs.
The aim of this project is to develop an HTS amenable assay and appropriate secondary assays to identify and characterize REV-ERBa ligands. Identification of REV-ERB ligands is essential to address the physiological function of these receptors. Additionally, due to the critical role that the REV-ERBs play in regulation of lipid and glucose metabolism, REV-ERBa ligands may be used as drugs that target disorders associated with dysregualtion of metabolic pathways including type 2 diabetes and cardiovascular disease.

Public Health Relevance

REV-ERB1 is a nuclear hormone receptor that plays critical role in control of lipid and glucose metabolism and the circadian rhythm.
The aim of this project is to develop assays to be used to identify REV-ERB1 ligands in a high throughput screen. Identification of REV-ERB1 ligands is essential to examine the physiological function of this receptor as well as to develop drugs that could be used to treat disorders such as type 2 diabetes and cardiovascular disease.