Role of the Mrg family of GPCRs in nociception

GPCRs Mrg 家族在伤害感受中的作用

• 批准号: 7008899
• 负责人: David J Anderson
• 金额: $ 107.98万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-19 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008899
• 关键词: analgesia; biological signal transduction; cell surface receptors; gene expression; genetically modified animals; laboratory mouse; ligands; neural transmission; neuroanatomy; neurogenetics; pain; protein structure function; receptor binding; receptor expression

Chronic pain is a serious health problem that has remained largely refractory to therapeutic intervention. The development of new pain therapeutics would be aided by a better understanding of the molecular and cellular mechanisms mediating nociception. The Mas-related genes (Mrgs) are a recently discovered, large family of G-protein coupled neuropeptide receptors (GPCRs) that are expressed with exquisite specificity in highly restricted subsets of nociceptive sensory neurons. The goal of this Program Project gram is to mount a concerted, interdisciplinary effort to understand the molecular function of differem Mrgs, the function of the neurons that express them, and the nature of the circuits in which these neurons participate. The project integrates the efforts of three laboratories with complementary expertise. The laboratory of David Anderson, which discovered the Mrgs, will utilize state-of-the art methods of mouse molecular genetics to generate and analyze strains of mice in which different Mrg genes have been deleted, and in which Mrg-expressing neurons can be inducibly ablated or silenced, or their second- and higher-order projections traced. These mice can also be used to prospectively identify Mrg-expressing neurons for physiological and molecular genetic analyses. The laboratory of Allan Basbaum is experienced in the behavioral, neuroanatomical, physiological and pharmacological analysis of nociception, and will collaborate with Anderson's group to thoroughly characterize the phenotypes of mice lacking different Mrg genes, or Mrg-expressing neurons, as well as in the analysis of Mrg synaptic connectivity. Because all Mrg-expressing cells are contained within the IB4-positive subset of nociceptive neurons, this project dovetails with the Basbaum laboratory's ongoing interest in understanding the function of this subpopulation in pain. The laboratory of Melvin Simon has expertise in the molecular genetic analysis of signal transduction by GPCRs and G-proteins. They will apply this expertise to characterize the pharmacology and mechanism of action of Mrgs, as well as to identify both endogenous and surrogate ligands for these receptors. In vitro culture of Mrg-expressing neurons will be employed to analyze and mechanistically dissect the influence of different candidate Mrg ligands, and idemify components of the intracellular signaling circuit. These studies may eventually lead to novel Mrg-based therapeutics for the treatment of pain in humans.

慢性疼痛是一种严重的健康问题，在很大程度上仍然难以治疗。新的疼痛疗法的发展将有助于更好地理解介导伤害感觉的分子和细胞机制。mas相关基因（Mrgs）是最近发现的一个g蛋白偶联神经肽受体（gpcr）大家族，在高度受限的伤害感觉神经元亚群中具有精致的特异性表达。本项目的目标是建立一个协调的、跨学科的努力，以了解不同Mrgs的分子功能