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.