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.

项目摘要在大脑中，控制代谢功能和喂养行为的关键焦点是黑色皮质素受体MC3R和MC4R。这些受体对两个配体有反应， α-甲状腺细胞刺激激素（A-MSH）和与Agouti相关蛋白（AGRP），以相反的方式行动以促进负能量平衡，分别。最近的研究表明，AGRP释放的重要性新陈代谢和体重稳态中的神经元。该程序的目标是了解AGRP动作的分子基础，从而实现了治疗的新策略与肥胖和代谢疾病有关的各种疾病。我们实验室的新发现大大重塑了我们对A-MSH和AGRP动作的理解。电流范式认为这些分子起作用来刺激或抑制产生第二使者营地。但是，使用蛋白质设计，我们证明了AGRP MCR结合核心以外的段中的突变对长期喂养，同时完全留下受体亲和力和cAMP抑制相对于野生型不变。此外，新的协作结果发现AGRP 通过营地促进向内整流钾通道的开放独立机制，这种效果直接取决于这些外围AGRP 细分市场。本应用程序的目标1将通过确定AGRP如何扩展这些研究序列和构象驱动钾通道电流。这将进行测试通过蛋白质设计，NMR结构的确定以及新的人通过整个外显子分析确定的AGRP肥胖连锁突变体。 AIM 2将检查如何 Syndecan-3，一种负电荷的膜结合蛋白聚糖，促进AgRP 信号。这将通过生物物理实验以及通过对野生型施用设计蛋白质的比较研究 Syndecan-3敲除小鼠，然后进行进食试验和脑组织成像。目标3 将扩大AGRP设计工作，以生产稳定的蛋白质来测试促进长期AGRP作用的蛋白水解抗性，并作为治疗的铅癌症恶病质，一种浪费状况，其特征是食欲极端丧失和瘦弱组织降解。