Investigating the Mechanisms Regulating RORgamma Activity

描述（由申请人提供）：代谢疾病，与蛋白质、碳水化合物和脂类的异常加工有关，是导致显著发病率和死亡率的原因。孤儿核受体，视黄酸受体相关的孤儿受体1、-2和-3 (ROR1、ROR2和ROR3)，在调节糖脂代谢、昼夜节律中起重要作用，并与多种疾病的病理有关，包括骨质疏松症、自身免疫性疾病、癌症和肥胖。对ROR1缺失小鼠的详细检查揭示了其在调节代谢途径（包括脂质代谢）中的重要作用。ROR3在Th17细胞发育中的重要作用以及与某些自身免疫性疾病的关联已被广泛评估。然而，对ROR3在其他细胞类型中的作用及其作用机制知之甚少。我们已经确定了ROR3的内源性功能配体（7-氧合甾醇）。此外，我们最近发表了苯磺酰胺肝X受体（LXR）激动剂T0901317也是ROR3的高亲和力合成配体。7-氧合甾醇（71-羟基胆固醇、72-羟基胆固醇和7-酮胆固醇）在人体中起着重要的生理和病理作用。长期目标是确定这些配体在调节ROR3活性中的作用。我们假设7-氧合甾醇是调节ROR3介导的细胞过程的关键配体。我们的假设将在以下特定目的中进行检验：特定目的1将确定ROR3对各种甾醇的特异性；特异性Aim 2将确定合成配体在ROR3上的特异性；在Specific Aim 3中，我们将确定天然和合成配体对ROR3调节的生理过程的影响。这些研究对于我们理解配体如何协调ROR3调节功能至关重要。配体调节的核激素受体已被明确地证明是药物开发的有效靶点。我们预测这些研究将为针对ROR3的新疗法治疗代谢紊乱提供基础。

DESCRIPTION (provided by applicant): Metabolic diseases, associated with abnormal processing of proteins, carbohydrates, and lipids, are the cause of significant morbidity and mortality. The orphan nuclear receptors, retinoic acid receptor-related orphan receptors 1, -2, and -3 (ROR1, ROR2, and ROR3), play important roles in regulating glucose and lipid metabolism, circadian rhythm, and have been implicated in the pathology of several diseases, including osteoporosis, autoimmune diseases, cancer, and obesity. Detailed examination of mice deficient in ROR1 has revealed a significant amount of information regarding its role in regulating metabolic pathways, including lipid metabolism. ROR3 has been extensively evaluated in regards to its essential role in Th17 cell development and association with certain autoimmune diseases. However, little is known about ROR3's role in other cell types or its mechanism of action. We have identified endogenous, functional ligands (7- oxygenated sterols) for ROR3. Additionally, we recently published that the benzenesulfoamide liver X receptor (LXR) agonist T0901317 is also a high affinity synthetic ligand for ROR3. 7-oxygenated sterols (71-hydroxycholesterol, 72- hydroxycholesterol, and 7-ketocholesterol) play important physiological and pathological roles in humans. The long-term objective is to determine the role of these ligands in regulating the activity of ROR3. We hypothesize that 7-oxygenated sterols are key ligands that regulate ROR3 mediated cellular processes. Our hypothesis will be tested in the following specific aims: Specific Aim 1 will determine the specificity of ROR3 for various sterols; Specific Aim 2 will determine the specificity of synthetic ligands on ROR3; and in Specific Aim 3 we will determine the effects of natural and synthetic ligands on ROR3 regulated physiological processes. These studies are essential for our understanding of how ligands may coordinate ROR3 regulated functions. Ligand-regulated nuclear hormone receptors have been definitively shown to be effective targets for the development of pharmaceuticals. We predict that these studies will provide the basis for novel therapeutics targeting ROR3 for the treatment of metabolic disorders. PUBLIC HEALTH RELEVANCE: The orphan nuclear receptors, retinoic acid receptor-related orphan receptors 1, -2, and -3 (ROR1, ROR2, and ROR3), play important roles in regulating glucose and lipid metabolism, circadian rhythm, and have been implicated in the pathology of several diseases, including osteoporosis, autoimmune diseases, cancer, and obesity. We have identified endogenous functional ligands (7-oxygenated sterols) for ROR3 and while ROR3 has been extensively evaluated in regards to its role in Th17 cell development and association with certain autoimmune diseases, little is known about ROR3's role in other cell types or its mechanism of action. Ligand- regulated nuclear hormone receptors have been definitively shown to be effective targets for the development of pharmaceuticals and we predict that our proposed studies may provide the basis for novel therapeutics targeting ROR3 for treatment of metabolic diseases.