Identification of Rev-Erb alpha/beta nuclear receptor modulators

Rev-Erb α/β 核受体调节剂的鉴定

• 批准号: 8671893
• 负责人: FRAYDOON RASTINEJAD
• 金额: $ 52.98万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671893
• 关键词: Animals; Behavior; Binding; Biochemical; Biological Assay; Blood - brain barrier anatomy; Carbohydrates; Cataloging; Catalogs; Cells; Cellular Assay; Chemicals; Chemistry; Cholesterol; Cholesterol Homeostasis; Circadian Rhythms; Consensus; DNA; DNA Binding; DNA Binding Domain; Diabetes Mellitus; Diet; Dose; Energy Metabolism; Ensure; Enzymes; Equilibrium; Fatty Acids; Fatty acid glycerol esters; Food; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genomics; Glucose; Glucose Intolerance; Glycolysis; Goals; Health; Heme; Homeostasis; Hormones; Human; Hyperlipidemia; Hypothalamic structure; Laboratories; Lead; Length; Libraries; Ligand Binding; Ligand Binding Domain; Ligands; Lipids; Mammals; Measures; Metabolic; Metabolism; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Organ; Organism; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Plasma; Proteins; Reporter; Response Elements; Sleep Wake Cycle; Specificity; Structure; System; Therapeutic; Time; Tissues; Triglycerides; Work; assay development; base; blood glucose regulation; circadian pacemaker; drug discovery; gene repression; glucose metabolism; glucose output; high throughput screening; hypercholesterolemia; innovation; insulin sensitivity; lipid biosynthesis; lipid metabolism; member; novel; oxidation; programs; receptor; receptor binding; response; screening; transcription factor

DESCRIPTION: In mammals, energy homeostasis requires the carefully timed orchestration of numerous metabolic processes. An endogenous circadian timing system ensures that metabolic enzymes are produced at just the right time within the day-night cycle to match the organism's food availability and fuel needs. Lipid, carbohydrate and glucose balance, as well as the secretion of hormones are all recognized to be under circadian control. Altering the sleep-wake cycles in humans causes metabolic disturbances, including reduced insulin sensitivity and glucose intolerance. In peripheral tissues and organs, the timing of gene expression involves transcription factors including the core clock components and the nuclear receptors Rev-Erbα and Rev-Erbß. The Rev-Erbs directly regulate the expression of many of the core clock components, but also act as master transcriptional regulators of lipid balance, adipogenesis, and glucose output. Similar to other nuclear receptors, the Rev-Erbs contain an internal hydrophobic cavity within their ligand binding domains (LBDs) that can be exploited for drug discovery. We previously identified heme as the endogenous ligand for the Rev-Erbs, and showed that reversible heme binding regulates their transcriptional activities. More recently, a single molecular class of Rev-Erbα/ß modulators was developed and shown to significantly alter the lipid and glucose gene programs in animals. Diet-induced obese animals treated with Rev-Erb modulators display remarkably reduced fat mass and improvements in their lipid and cholesterol profiles and plasma glucose levels. We now seek to identify many new classes of Rev-Erb binding molecules, including modulators that act specifically on each of the Rev- Erbα and Rev-Erbß receptors. To find such modulators, we have developed and optimized a novel high- throughput assay that efficiently identifies molecules that bind within the LBDs, or within the domain-domain junctions of their quaternary structures. We propose to carry out a pair of high-throughput screening campaigns using the MLPCN library and a battery of secondary/confirmatory assays and gene expression studies that identify the most promising Rev-Erbα/ß modulators. The overall goal is to find and develop molecules with potential benefits for obesity, diabetes, and hyperlipidemia.

描述：在哺乳动物中，能量稳态需要精心安排许多代谢过程的时间。内源性昼夜节律计时系统确保代谢酶在昼夜循环中的正确时间产生，以匹配生物体的食物供应和燃料需求。脂质、碳水化合物和葡萄糖平衡以及激素的分泌都被认为是在昼夜节律控制下。改变人类的睡眠-觉醒周期会导致代谢紊乱，包括胰岛素敏感性降低和葡萄糖耐受不良。在外周组织和器官中，基因表达的时序涉及转录因子，包括核心时钟组件和核受体Rev-Erbα和Rev-Erbb 3。Rev-Erbs直接调节许多核心时钟成分的表达，但也作为脂质平衡，脂肪生成和葡萄糖输出的主要转录调节因子。与其他核受体类似，Rev-Erb在其配体结合结构域（LBD）内含有内部疏水腔，可用于药物发现。我们以前确定血红素作为内源性配体的Rev-Erbs，并表明，可逆血红素结合调节其转录活性。最近，开发了一种单一分子类别的Rev-Erbα/β调节剂，并显示出显著改变动物中的脂质和葡萄糖基因程序。用Rev-Erb调节剂治疗的饮食诱导的肥胖动物显示出显著减少的脂肪量以及它们的脂质和胆固醇分布和血浆葡萄糖水平的改善。我们现在试图鉴定许多新类型的Rev-Erb结合分子，包括特异性作用于每种Rev-Erb α和Rev-Erb α受体的调节剂。为了找到这样的调节剂，我们已经开发并优化了一种新的高通量测定法，其有效地鉴定在LBD内或在其四级结构的结构域-结构域连接内结合的分子。我们建议使用MLPCN文库进行一对高通量筛选活动，并进行一系列二级/确证性试验和基因表达研究，以确定最有前途的Rev-Erbα/β调节剂。总体目标是发现和开发对肥胖、糖尿病和高脂血症具有潜在益处的分子。