Understanding the mechanism of action and pathophysiological function of the NOR1 and Nur77 orphan nuclear receptors

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Nuclear hormone receptors (NRs) function as ligand-hormone activated transcription factors that regulate gene expression involved in reproduction, development and metabolism. Dysfunctional hormonal signalling, and inappropriate NR function results in reproductive disorders, inflammation, cancer, diabetes, and cardiovascular disease. The significance of NRs in disease is underscored by the range of pharmacopoeia developed for the treatment of NR associated disorders. Orphan NRs belong to the superfamily on the basis of their sequence identity, however, the endogenous signaling molecules which bind to these proteins are unknown. The orphan NRs Nur77, NURR1, and NOR1, functions as stress response genes which are induced by a wide range of physiological stimuli Furthermore, the NR4A subgroup of receptors has been implicated in carcinogenesis, neurological disorders; inflammation, diabetes and atherogenesis. The objective of this proposal is to examine the molecular mechanisms that control the regulation of gene expression by the orphan nuclear receptors, Nur77 and NOR-1. Furthermore, we will investigate the pathophysiological function of NOR-1 and Nur77 in muscle. Nur77 and NOR-1 are expressed in skeletal muscle. This major mass tissue accounts for ~40% of total body weight and, is a major site of glucose and fat metabolism. Consequently, this peripheral tissue plays a significant role in insulin sensitivity, and the blood lipid profile. Furthermore, a collaboration with industry has identified NOR-1 as an insulin responsive gene in muscle, which becomes hyper-sensitive to insulin induction in diabetic patients. Additionally, we have exciting evidence that the anti-neoplastic purine anti-metabolite, 6-mercaptopurine activates the NR4A subgroup. Nur77 and NOR-1 represent an exciting challenge, and unlocking the molecular mechanisms that NOR-1-dependent transcription provides the opportunity for identifying novel signaling pathways, and therapeutics.