The human nuclear hormone receptor (NHR) superfamily 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. The retinoic acid receptor related orphan receptors (RORs) are members of the NHR superfamily and include three receptors (RORa [NR1F1], ROR? [NR1F2] and ROR? [NR1F3]) that have diverse functions and patterns of expression. No functional natural ligands have been characterized for these 3 receptors and, additionally, there are no validated synthetic ligands to use as probes to characterize the biological roles of RORs currently exist. Thus, development of screening assays for identification of ROR ligands is essential to address the physiological function of these receptors. This proposal focuses on development of screening assays to identify specific ROR? ligands. ROR? is a particularly interesting NHR and putative drug target because of the role it plays in the biology of an effector-memory CD4+ T cell lineage known at the Th17 cell, which produces IL-17. Th17 cells have an important role in the pathophysiology of autoimmunity and tissue inflammation and ROR? is known to regulate the differentiation of Th17 cells as well as direct the expression of IL-17. Thus, inhibitors of ROR? function that inhibit Th17 cell proliferation may be effective for treatment of diseases involving inflammation and autoimmunity. In order to identify ROR? chemical tools that could be used to investigate the role of ROR? in these processes as well as to validate the possibility of targeting this receptor for the treatment of immune disorders, we propose the following specific aims: (1) Develop and validate a biochemical assay to detect ROR? ligands in a high-throughput screen format;(2) Develop and validate secondary assays for the purpose of characterizing """"""""hits"""""""" identified in a ROR? high througput screen;and (3) Perform a validating screen of the ROR? assay flow scheme using the LOPAC 1280 chemical library.
The human nuclear hormone receptor (NHR) superfamily 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. This proposal focuses on development of screening assays to identify specific ROR? ligands. Inhibitors of ROR? may be effective for treatment of diseases involving inflammation and autoimmunity.
| Wang, Yongjun; Kumar, Naresh; Crumbley, Christine et al. (2010) A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol). Biochim Biophys Acta 1801:917-23 |
| Wang, Yongjun; Kumar, Naresh; Solt, Laura A et al. (2010) Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J Biol Chem 285:5013-25 |
