Role of the Mrg family of GPCRs in nociception

慢性疼痛是一个严重的健康问题，在很大程度上仍然难以进行治疗干预。更好地了解介导伤害性感觉的分子和细胞机制将有助于新疼痛疗法的发展。Mas相关基因是新近发现的一个G蛋白偶联神经肽受体大家族，在高度受限的伤害性感觉神经元亚群中具有极高的特异性。该计划项目的目标是开展一项协调的、跨学科的努力，以了解不同MRGS的分子功能、MERG的功能 表达它们的神经元，以及这些神经元参与的电路的性质。该项目整合了三个具有互补专业知识的实验室的努力。发现MRG的大卫·安德森的实验室将利用最先进的小鼠分子遗传学方法来产生和分析不同MRG基因已被缺失的小鼠品系，在这些品系中，表达MRG的神经元可以被诱导消融或沉默，或者追踪它们的二阶和更高阶投影。这些小鼠还可以用于前瞻性地鉴定表达MRG的神经元，用于生理和分子遗传学分析。 Allan Basbaum的实验室在伤害性感受的行为、神经解剖学、生理学和药理学分析方面经验丰富，并将与Anderson的团队合作，彻底表征缺乏不同MRG基因或MRG表达神经元的小鼠的表型，以及分析MRG突触连接。由于所有表达MRG的细胞都包含在IB4阳性的伤害性神经元亚群中，该项目与巴斯鲍姆实验室正在进行的了解这一亚群在疼痛中的功能的兴趣相吻合。梅尔文·西蒙的实验室在GPCRs和G蛋白信号转导的分子遗传分析方面拥有专业知识。他们将把这一专业知识应用于 描述MRGS的药理作用和作用机制，以及鉴定这些受体的内源性和替代配体。体外培养表达MRG的神经元将被用来分析和机械解剖不同候选MRG配体的影响，并识别细胞内信号通路的组成部分。这些研究可能最终导致基于MRG的治疗人类疼痛的新疗法。

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.