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Molecular determinants of melanocortin 4 receptor for selective agonist binding

黑皮质素 4 受体选择性激动剂结合的分子决定因素

基本信息

批准号：
7669106
负责人：
YINGKUI YANG
金额：
$ 7.25万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-07 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7669106
关键词：
ART protein Adult Affinity Agonist American Amino Acid Sequence Amino Acids Binding Body Weight Brain Child Coronary Arteriosclerosis Data Desire for food Development Diabetes Mellitus Eating Energy Metabolism Etiology Face Food Intake Regulation Future Goals Health Human Hypertension Hypothalamic structure Ligand Binding Ligands Medical Melanocortin 4 Receptor Melanocyte stimulating hormone Metabolic Molecular Molecular Probes Mutation Nutritional Obesity Peptide Receptor Peptides Photoaffinity Labels Physiological Play Prevalence Public Health Receptor Signaling Regulation Research Research Personnel Risk Role Satiation Signal Transduction Societies Stroke Structure System Testing Therapeutic Transmembrane Domain United States base design energy balance feeding in vivo insight novel obesity in children obesity treatment receptor receptor function seven-transmembrane G-protein-coupled receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Childhood obesity is one of the major health threats for modern American society. A major concern regarding childhood obesity is that obese children face an increased risk of diabetes mellitus, hypertension, stroke and coronary artery diseases. Obesity is a particularly challenging medical condition to treat because of its multi-factorial etiology and existing therapeutic limitations. The melanocortin-4 receptor (MC4R) has been identified to play a key role in the regulation of food intake and body weight. Our long term goal is to elucidate the molecular basis of hMC4R responsible for ligand binding and signaling as a necessary prerequisite to the development of selective MC4R nonpeptide agonist for therapeutic treatment of obesity. We hypothesize that unique amino acid residues in the transmembrane domains of hMC4R are involved in the selective MC4R agonist binding. To test this hypothesis, we will utilize 1) novel photoaffinity labeling of selective agonist to examine the direct interaction between the ligand and MC4R, and 2) identify the direct interactions between selective agonist and MC4R using reciprocal ligand and receptor residue exchange. Our proposed studies will provide the finest level of molecular detail for ligand binding, receptor signaling and will provide valuable information for designing selective MC4R agonists that may be used in the treatment of human obesity. Obesity is one of the major health threats facing modern American society. This R03 application is to explore the molecular basis of melanocorin 4 receptor responsible for agonist activity which can be used to develop new therapuetic approach for obesity.

描述（由申请人提供）：儿童肥胖是现代美国社会的主要健康威胁之一。儿童肥胖的一个主要问题是，肥胖儿童患糖尿病、高血压、中风和冠状动脉疾病的风险增加。肥胖是一个特别具有挑战性的医疗条件，以治疗，因为它的多因素病因和现有的治疗局限性。黑皮质素-4受体（MC 4 R）已被确定在调节食物摄入和体重中起关键作用。我们的长期目标是阐明负责配体结合和信号传导的hMC 4 R的分子基础，作为开发用于治疗性治疗肥胖的选择性MC 4 R非肽激动剂的必要前提。我们推测，独特的氨基酸残基在跨膜结构域的hMC 4 R参与选择性MC 4 R激动剂结合。为了验证这一假设，我们将利用1）选择性激动剂的新型光亲和标记来检查配体与MC 4 R之间的直接相互作用，以及2）使用相互配体和受体残基交换来鉴定选择性激动剂与MC 4 R之间的直接相互作用。我们提出的研究将提供配体结合、受体信号传导的最精细的分子细节，并将为设计可用于治疗人类肥胖的选择性MC 4 R激动剂提供有价值的信息。肥胖是现代美国社会面临的主要健康威胁之一。该R 03应用是探索负责激动剂活性的黑色素4受体的分子基础，其可用于开发肥胖症的新治疗方法。