Identification of Rev-Erb alpha/beta nuclear receptor modulators

Rev-Erb α/β 核受体调节剂的鉴定

基本信息

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
项目类别：
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

项目摘要

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，能量稳态需要仔细的定时编排，众多代谢过程。内源性昼夜节律定时系统可确保在昼夜周期内适当的时间生产代谢酶，以符合生物体的食物可用性和燃料需求。脂质，碳水化合物和葡萄糖平衡以及激素的分泌均被认为是昼夜节律控制的。改变人类的睡眠效果周期会引起代谢性疾病，包括降低胰岛素敏感性和葡萄糖intlerance。在外围组织和器官中，基因表达的时机涉及转录因子，包括核心时钟成分和核受体Rev-ERBα和Rev-erbß。 Rev-ERB直接调节许多核心时钟成分的表达，但也充当脂质平衡，脂肪生成和葡萄糖输出的主转录调节剂。与其他核受体类似，Rev-ERB在其配体结合结构域（LBD）内包含一个内部疏水腔，可以探索以进行药物发现。我们先前鉴定出血红素为Rev-ERB的内源配体，并表明可逆的血红素结合调节其转录活性。最近，开发了单个分子类Rev-ERBα/ß调节剂，并证明可以显着改变动物中脂质和葡萄糖基因程序。用Rev-ERB调节剂处理的饮食诱导的肥胖动物显示出脂肪质量的降低以及脂质和胆固醇谱和血浆葡萄糖水平的改善。现在，我们试图确定许多新的Rev-ERB结合分子，包括专门针对Rev-erBα和Rev-Erbß受体的调节剂。为了找到这样的调节剂，我们开发了并优化了一种新型的高通量测定法，该测定方法有效地识别了在LBD中或其Quaternary结构的结构域连接中结合的分子。我们建议使用MLPCN库以及一系列的二级/验证性测定和基因表达研究进行一对高通量筛选活动，以确定最有希望的Rev-ERBα/ß调节剂。总体目标是找到和开发具有肥胖，糖尿病和高脂血症潜在益处的分子。