Investigating the Mechanisms Regulating RORgamma Activity

研究调节 RORgamma 活性的机制

• 批准号: 8205652
• 负责人: Laura A Solt
• 金额: $ 5.39万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205652
• 关键词: 7-ketocholesterol; Affinity; Agonist; Autoimmune Diseases; Binding; Carbohydrates; Cell physiology; Cells; Circadian Rhythms; Development; Disease; Hepatocyte; Human; Hydroxycholesterols; In Vitro; Ligands; Lipids; Liver; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Morbidity - disease rate; Mus; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Obesity; Orphan; Osteoporosis; Pathology; Pharmacologic Substance; Physiological; Physiological Processes; Play; Process; Proteins; Publishing; RORA gene; Retinoic Acid Receptor; Role; Specificity; Sterols; Testing; Work; base; cell type; cofactor; glucose metabolism; in vivo; lipid metabolism; mortality; mouse model; new therapeutic target; public health relevance; receptor

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.

描述（由申请人提供）：与蛋白质、碳水化合物和脂质的异常加工相关的代谢疾病是显着发病和死亡的原因。孤儿核受体、视黄酸受体相关孤儿受体 1、-2 和 -3（ROR1、ROR2 和 ROR3）在调节葡萄糖和脂质代谢、昼夜节律中发挥重要作用，并与以下疾病的病理学有关：多种疾病，包括骨质疏松症、自身免疫性疾病、癌症和肥胖症。对 ROR1 缺陷小鼠的详细检查揭示了有关其在调节代谢途径（包括脂质代谢）中的作用的大量信息。 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得到广泛评估。然而，人们对 ROR3 在其他细胞类型中的作用或其作用机制知之甚少。我们已经鉴定出 ROR3 的内源性功能配体（7-氧化甾醇）。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-氧化甾醇（71-羟基胆固醇、72-羟基胆固醇和7-酮胆固醇）在人类中发挥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-氧化甾醇是调节 ROR3 介导的细胞过程的关键配体。我们的假设将在以下具体目标中得到检验： 具体目标 1 将确定 ROR3 对各种甾醇的特异性；具体目标 2 将确定合成配体对 ROR3 的特异性；在具体目标 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。这些研究对于我们了解配体如何协调 ROR3 调节功能至关重要。配体调节的核激素受体已被明确证明是药物开发的有效靶标。我们预测这些研究将为针对 ROR3 治疗代谢性疾病的新疗法提供基础。 公共卫生相关性：孤儿核受体、视黄酸受体相关孤儿受体 1、-2 和 -3（ROR1、ROR2 和 ROR3）在调节葡萄糖和脂质代谢、昼夜节律中发挥重要作用，并与涉及多种疾病的病理学，包括骨质疏松症、自身免疫性疾病、癌症和肥胖症。我们已经鉴定出 ROR3 的内源性功能配体（7-氧化甾醇），虽然 ROR3 在 Th17 细胞发育中的作用以及与某些自身免疫性疾病的关联已得到广泛评估，但对 ROR3 在其他细胞类型中的作用或其机制知之甚少的行动。配体调节的核激素受体已被明确证明是药物开发的有效靶标，我们预测我们提出的研究可能为针对 ROR3 治疗代谢疾病的新型疗法提供基础。