REGULATION OF ENERGY BALANCE BY MELANOCORTIN ANTAGONISTS

黑皮质素拮抗剂对能量平衡的调节

• 批准号: 6635031
• 负责人: Gregory Stefan Barsh
• 金额: $ 17.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-25 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635031
• 关键词: basal metabolism; bioenergetics; biological signal transduction; body weight; eating; expression cloning; gene expression; gene interaction; gene mutation; gene targeting; genetically modified animals; genotype; hormone inhibitor; hormone receptor; in situ hybridization; laboratory mouse; melanocyte; melanocyte stimulating hormone; nutrition related tag; obesity; pigmentation; receptor binding; receptor sensitivity; secretory protein; tissue /cell culture

Agouti protein and Agouti-related protein (Agrp) are novel ligands for the melanocortin 1 receptor (Mc1r) and Mc4r, respectively, and are thought to exert their physiologic effects by inhibition of alpha-MSH binding, and by a second, as yet undefined, mechanism that is mediated through melanocortin receptors but is distinct from melanocortin displacement. Previously existing mutations of Agouti and the Mc1r have provided some of the critical tools and key insights for understanding these pathways; another coat color mutation, mahogany, has been implicated in Agouti protein and Agrp signaling because it suppresses the effects of Agouti on both pigmentation and obesity. Double mutant studies indicate that mahogany is genetically downstream of Agouti transcription but genetically upstream of melanocortin receptor signaling. To investigate how Agrp and the gene mutated in mahogany are involved in the normal regulation of body weight, we propose to 1) Identify the mahogany gene by positional cloning and determine it's pattern of RNA and protein expression; 2) construct a mahogany null allele and determine its effects on obesity induced by ectopic expression of Agrp, or by deficiency for the Mc4r; 3) use a natural cell culture model for mahogany gene action established with primary melanocytes to investigate whether mahogany affects melanocortin receptor number, ligand affinity, or coupling to downstream effectors; and 4) develop a quantitative binding assay for Agrp to determine if mahogany acts at the level of ligand processing, stabilization, or cell surface binding.

Agouti蛋白和与Agouti相关的蛋白（AGRP）分别是黑色素皮质素1受体（MC1R）和MC4R的新型配体，并且被认为可以通过抑制α-MSH结合的抑制来造成其生理效应，而第二种是通过未定义的机制来介导的，但它却被脱离了糖尿病的受体。以前现有的Agouti和MC1R突变为理解这些途径提供了一些关键工具和关键见解。另一个外套的颜色突变是桃花心木，与Agouti蛋白和AGRP信号传导有关，因为它抑制了Agouti对色素沉着和肥胖的影响。双重突变研究表明，桃花心木在基因转录的基因下游，但在遗传上是黑色素皮质素受体信号传导的上游。为了研究桃花心木中的AGRP和基因如何参与体重的正常调节，我们建议1）通过位置克隆确定桃花心木基因，并确定其RNA和蛋白质表达的模式； 2）构建桃花心木无效的等位基因，并确定其对AGRP异位表达或MC4R缺乏引起的肥胖的影响； 3）使用与原代黑素细胞建立的桃花心木基因作用的自然细胞培养模型研究桃花心木是影响黑素皮质素受体的数量，配体亲和力还是与下游效应子耦合； 4）为AGRP开发定量结合测定法，以确定桃花心木是在配体加工，稳定或细胞表面结合水平上作用的。

项目成果

The role of insulin receptor substrate 2 in hypothalamic and beta cell function.

• DOI: 10.1172/jci24445
• 发表时间: 2005-04
• 期刊: The Journal of clinical investigation
• 作者: A. I. Choudhury;H. Heffron;Mark A. Smith;Hind Al‐Qassab;Allison W. Xu;C. Selman;M. Simmgen;M. Clements;M. Claret;G. Maccoll;D. C. Bedford;K. Hisadome;I. Diakonov;Vazira Moosajee;Jimmy D Bell;J. Speakman;R. Batterham;G. Barsh;M. Ashford;D. Withers

Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding.

• DOI: 10.1210/en.2006-1119
• 发表时间: 2007
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Allison W. Xu;Linda Ste-Marie;C. Kaelin;G. Barsh

Electrostatic Similarity Analysis of Human β-Defensin Binding in the Melanocortin System.

黑皮质素系统中人类β-防御素结合的静电相似性分析。

• DOI: 10.1016/j.bpj.2015.09.005
• 发表时间: 2015
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Nix,MatthewA;Kaelin,ChristopherB;Palomino,Rafael;Miller,JillianL;Barsh,GregoryS;Millhauser,GlennL
• 通讯作者: Millhauser,GlennL

PI3K integrates the action of insulin and leptin on hypothalamic neurons.

• DOI: 10.1172/jci24301
• 发表时间: 2005-04
• 期刊: The Journal of clinical investigation
• 作者: Allison W. Xu;C. Kaelin;K. Takeda;S. Akira;M. Schwartz;G. Barsh

Effects of hypothalamic neurodegeneration on energy balance.

• DOI: 10.1371/journal.pbio.0030415
• 发表时间: 2005-12
• 期刊: PLOS BIOLOGY
• 影响因子: 9.8
• 作者: Xu, Allison Wanting;Kaelin, Christopher B;Morton, Gregory J;Ogimoto, Kayoko;Stanhope, Kimber;Graham, James;Baskin, Denis G;Havel, Peter;Schwartz, Michael W;Barsh, Gregory S
• 通讯作者: Barsh, Gregory S