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Molecular Mechanisms of AgRP Signaling

AgRP 信号转导的分子机制

基本信息

批准号：
9919555
负责人：
GLENN L MILLHAUSER
金额：
$ 42.41万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919555
关键词：
ART protein Affinity Amino Acid Sequence Animals Anorexia Appetite Stimulants Behavior Binding Biological Biophysics Blood Body Weight Bolus Infusion Brain Cell surface Charge Chemicals Cholesterol Collaborations Complex Cone Coronary Arteriosclerosis Coupling Cyclic AMP Cyclization Cystine Diabetes Mellitus Disease Electrophysiology (science)Energy Intake Energy Metabolism Enhancers Family Feeding behaviors G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Glycosaminoglycans Goals Homeostasis Human Hypertension Hypothalamic structure Image Injections Knockout Mice Lead Leptin Ligand Binding Ligands Link Malignant Neoplasms Mediating Melanocortin 3 Receptor Melanocortin 4 Receptor Membrane Metabolic Metabolic Control Metabolic Diseases Metabolism Molecular Molecular Conformation Mutation Neurons Obesity Peptides Peripheral Pharmacology Physiological Play Potassium Channel Production Protein Conformation Protein Engineering Proteins Proteoglycan Proteolysis Public Health Publishing Rattus Regulation Research Resistance Role Scaffolding Protein Second Messenger Systems Signal Transduction Signaling Protein Societies Structure Surface System Techniques Testing Thermodynamics Thinness Time Tissue imaging Tissues Variant Vertebral column Wasting Syndrome Weight Gain Work alpha-Melanocyte stimulating hormone analog appetite loss base brain tissue cancer cachexia crosslink design energy balance exome exome sequencing experimental study feeding hormonal signals improved in vivo inhibitor/antagonist inward rectifier potassium channel melanocortin receptor member mutant neural circuit novel novel therapeutic intervention nutrient deprivation programs protein structure receptor response structural biology syndecan syndecan 3

项目摘要

Project Summary In the brain, key focal points for control of metabolic function and feeding behavior are melanocortin receptors MC3R and MC4R. These receptors respond to two ligands, alpha-melanocyte stimulating hormone (a-MSH) and the agouti-related protein (AgRP), which act in opposite ways to promote negative and positive energy balance, respectively. Recent research demonstrates the profound importance of AgRP releasing neurons in metabolism and body weight homeostasis. The goal of this program is to understand the molecular basis of AgRP action, thus enabling new strategies for treating diverse conditions linked to obesity and metabolic diseases. New findings from our lab are significantly reshaping our understanding of a-MSH and AgRP action. The current paradigm posits that these molecules act to stimulate or suppress production of the cAMP second messenger. However, using protein design, we demonstrated that AgRP mutations in segments outside of the MCR binding core exert a profound influence on long term feeding, while leaving receptor affinity and cAMP suppression completely unchanged relative to wild-type. Moreover, new collaborative results find that AgRP promotes the opening of inward rectifying potassium channels through a cAMP independent mechanism, an effect that is directly dependent on these peripheral AgRP segments. Aim 1 of this application will expand these studies by identifying how AgRP sequence and conformation drive potassium channel currents. This will be tested through protein design, NMR structure determination, as well as with a new human AgRP obesity-linked mutant identified by whole exome analysis. Aim 2 will examine how syndecan-3, a negatively charged, membrane bound proteoglycan, facilitates AgRP signaling. This will be accomplished with biophysical experiments and through comparison studies where designed proteins are administered to wild-type and syndecan-3 knockout mice, followed by feeding trials and brain tissue imaging. Aim 3 will expand on AgRP design efforts to produce stable proteins to test the role of proteolytic resistance in promoting long-term AgRP action, and as leads for treating cancer cachexia, a wasting condition characterized by extreme loss of appetite and lean tissue degradation.

项目总结