Identification of a novel bioactive peptide

新型生物活性肽的鉴定

• 批准号: 6670535
• 负责人: HANS-PETER NOTHACKER
• 金额: $ 14.39万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6670535
• 关键词: behavior test; bombesin; bombesin like peptide; cell line; cell surface receptors; eating; laboratory rat; ligands; neuropeptide receptor; protein localization; protein purification; protein structure function; receptor binding; receptor expression

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) constitute the largest gene family in the human genome and accumulate the most successful biochemical targets for therapeutic drugs. The natural ligands of about 140 GPCRs are unknown and they are thus called "orphan" receptors. Identification of these natural ligands forms the crucial step to start studying their function and holds the potential for development of novel pharmaceutical drugs. We have developed a strategy to isolate such natural ligands by expressing the cloned receptors in suitable cell lines and monitoring activation of the receptors after adding fractions of tissue extracts. This novel strategy will ultimately allow us to purify the active molecules and determine their structure. In this application, we propose to apply this highly innovative technique to isolate, identify and characterize the natural ligand of the orphan receptor bombesin subtype-3 (BRS-3) that is still elusive. BRS-3 receptor is expected to play an important role in integrating and modulating the complex physiology underlying feeding as evidenced by the fact that mice devoid of BRS-3 receptor are hyperphagic, hypometabolic and develop an obese phenotype. This receptor does not bind the two known mammalian bombesin counterparts of the frog peptide neuromedin B and gastrin-releasing peptide that bind to the other two bombesin receptor subtypes (BB-1 and 2). Following the isolation of the natural ligand, we will characterize the pharmacological effects, study the Subsequently, we propose to study the BRS-3 ligand in a behavioral feeding assay in order to determine its mode of action. The BRS-3 ligands will prove as an invaluable tool to answer the functional significance and understand the physiological role of the BRS-3 system in the regulation of energy balance.

描述（由申请人提供）：G蛋白偶联受体（GPCR）构成人类基因组中最大的基因家族，并积累了治疗药物最成功的生化靶标。约140种GPCR的天然配体是未知的，因此它们被称为“孤儿”受体。这些天然配体的鉴定形成了开始研究其功能的关键步骤，并具有开发新型药物的潜力。我们已经开发了一种策略，通过在合适的细胞系中表达克隆的受体，并在加入组织提取物组分后监测受体的活化来分离这种天然配体。这种新的策略最终将使我们能够纯化活性分子并确定它们的结构。在本申请中，我们建议应用这种高度创新的技术来分离，鉴定和表征孤儿受体蛙皮素亚型-3（BRS-3）的天然配体，这仍然是难以捉摸的。预期BRS-3受体在整合和调节作为进食基础的复杂生理学中起重要作用，如缺乏BRS-3受体的小鼠是高吞噬性、低代谢性和发展肥胖表型的事实所证明的。该受体不结合蛙肽神经介肽B和胃泌素释放肽的两种已知的哺乳动物蛙皮素对应物，所述蛙肽神经介肽B和胃泌素释放肽结合其它两种蛙皮素受体亚型（BB-1和2）。在分离天然配体之后，我们将表征药理作用，研究随后，我们建议在行为摄食测定中研究BRS-3配体，以确定其作用模式。BRS-3配体将被证明是回答功能意义和理解BRS-3系统在能量平衡调节中的生理作用的无价工具。