TRACE AMINE-ASSOCIATED RECEPTOR 1 IS A MODULATOR OF BRAIN MONOAMINERGIC SYSTEMS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 由于人类和啮齿类动物的微量胺受体在结构、亚型数量和脑分布上存在差异，我们推测非人类灵长类动物将为揭示微量胺亚型的生理和药理学相关性提供更合适的模型。在这方面，在非人灵长类动物和人类中，痕量胺相关受体1（TAAR 1）具有96%的序列同一性。为了建立探索TAAR亚型功能所需的基础信息，我们研究了非人灵长类动物TAAR亚型的结构、药理学、信号转导和脑分布。我们利用荧光素酶检测敏感不同的信号转导途径，揭示激动剂以及拮抗剂，阻断激动剂诱导的受体活化。我们利用实时荧光定量RT-PCR和免疫组织化学技术对TAAR亚型mRNA和蛋白在灵长类动物脑中的分布进行了定位，以确定哪些受体亚型在脑中表达。我们研究这个位点的遗传变异，以评估多态性是否可能与成瘾和其他精神疾病有关。我们的研究形成了在灵长类动物模型中研究微量胺受体的生理和药理学相关性的基础，并为开发治疗药物治疗成瘾和神经精神疾病提供了新的线索。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As human and rodent trace amine receptors diverge in structure, subtype number and brain distribution, we postulate that non-human primates will provide a more suitable model for uncovering the physiological and pharmacological relevance of trace amine subtypes. In this regard, there is a 96 percent sequence identity for Trace Amine Associated Receptor 1 (TAAR1) in non-human primate and human. To establish fundamental information needed to explore TAAR subtype function, we investigate non-human primate TAAR subtype structure, pharmacology, signal transduction and brain distribution. We utilize luciferase assays sensitive to different signal transduction pathways to uncover agonists as well as antagonists that block agonist-induced receptor activation. We map TAAR subtype mRNA and protein distribution in primate brain using real-time RT-PCR and immunohistochemistry, to discern which receptor subtypes are expressed in brain. We study genetic variation at this locus, to assess whether polymorphisms may be implicated in addiction and other psychiatric disorders. Our studies form the basis for investigating the physiological and pharmacological relevance of trace amine receptors in a primate model, and provide novel leads for developing therapeutic agents to treat addiction and neuropsychiatric disorders.