Development of ROR ligands for treatment of metabolic diseases

描述(由申请人提供)：与碳水化合物和脂类代谢异常相关的代谢性疾病是导致严重发病率和死亡率的原因。核受体(NR)超家族的几个成员通过其配体调节参与碳水化合物和脂肪代谢的关键基因的表达，这些配体包括脂肪酸、胆汁酸、胆固醇代谢物、类固醇激素和亲脂性维生素衍生物。我们已经确定了第一个以视黄酸受体相关的孤儿受体(RORA和Rory)为靶点的合成配体，这些受体以其调节糖和脂代谢的能力而被很好地表征。这是一项R24基金的申请，题为“建立糖尿病、内分泌学和L代谢疾病的跨学科协作团队科学”，我们建议的研究重点是使我们的研究团队能够集中精力开发口服活性的ROR配体，用于治疗糖尿病和/或肥胖。这些研究对于我们理解合成的ROR配体如何协调代谢途径，以及更广泛地确定ROR配体在治疗代谢综合征中是否有用是至关重要的。 相关性：我们提出的开发ROR靶向药物的研究可能为针对ROR的新疗法提供基础，用于治疗糖尿病、动脉粥样硬化和肥胖等代谢性疾病。

DESCRIPTION (provided by applicant): Metabolic diseases associated with abnormal metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality. Several members of the nuclear receptor (NR) superfamily regulate the expression of key genes involved in regulation of carbohydrate and lipid metabolism in response to their ligands, which include fatty acids, bile acids, cholesterol metabolites, steroid hormones, and lipophilic vitamin derivatives. We have identified the first synthetic ligands that target the retinoic acid receptor- related orphan receptors (RORa, and RORy), receptors that are well characterized for their ability to modulate glucose and lipid metabolism. This is an application for a R24 grant titled, "Seeding Collaborative Interdisciplinary Team Science in Diabetes, Endocrinology and l\/letabolic Diseases", and the focus of our proposed research is to enable our research team consisting of NR pharmacology, structural biology, metabolic disease pharmacology, drug metabolism and pharmacokinetics, and medicinal chemistry to focus on development of orally active ROR ligands for the treatment of diabetes arid/or obesity. These studies are essential for our understanding of how synthetic ROR ligands might coordinate metabolic pathways and more generally, determination of whether or not ROR ligands may be useful in the treatment of metabolic syndrome. RELEVANCE: Our proposed studies to develop ROR targeted drugs may provide the basis for novel therapeutics targeting the RORs for treatment of metabolic disorders such as diabetes, atherosclerosis and obesity.