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

核激素受体（Nuclear hormone receptor, NRs）是配体激素激活的转录因子，在生殖、发育和代谢过程中调控基因表达。激素信号功能失调和NR功能不适当导致生殖障碍、炎症、癌症、糖尿病和心血管疾病。为治疗NR相关疾病而制定的药典范围强调了NR在疾病中的重要性。孤儿rna在序列上属于超家族，然而，与这些蛋白结合的内源性信号分子是未知的。孤儿nrrs Nur77、NURR1和NOR1是应激反应基因，可被广泛的生理刺激诱导。此外，NR4A受体亚群与致癌、神经系统疾病；炎症、糖尿病和动脉粥样硬化。这一提案的目的是检查控制基因表达的调控的分子机制的孤儿核受体,Nur77 NOR-1。此外，我们将研究NOR-1和Nur77在肌肉中的病理生理功能。在骨骼肌Nur77和NOR-1表达。这个主要的肿块组织约占体重的40%，是葡萄糖和脂肪代谢的主要部位。因此,该外围组织发挥了重要作用,胰岛素敏感性,和血液血脂。此外，一项与工业界的合作已经确定了NOR-1是肌肉中的胰岛素应答基因，该基因对糖尿病患者的胰岛素诱导变得高度敏感。此外，我们有令人兴奋的证据表明抗肿瘤嘌呤抗代谢物6-巯基嘌呤激活NR4A亚群。Nur77和NOR-1代表了一个令人兴奋的挑战，并且揭示了NOR-1依赖转录的分子机制，为识别新的信号通路和治疗方法提供了机会。

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.