TAAR1 POLYMORPHISMS IN RHESUS MONKEYS

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。子项目和 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所在的机构。 恒河猴痕量胺相关受体1（TAAR 1）对广谱内源性胺（包括“痕量”胺β-苯乙胺和酪胺，以及常见的生物胺多巴胺、去甲肾上腺素和5-羟色胺）以及苯丙胺样精神兴奋剂产生反应， 包括冰毒在恒河猴脑中，我们已经表明，TAAR 1 mRNA表达在单胺能区域，并且TAAR 1与单胺能神经元中的单胺转运体共表达并调节单胺转运体。我们的研究表明，TAAR 1与单胺自身受体一起被普通生物胺沿着激活，但只有TAAR 1被甲基苯丙胺激活， 导致异常的cAMP积累，触发细胞磷酸化事件以及随之而来的单胺转运蛋白动力学功能失调。我们最近还发现，TAAR 1在恒河猴和人免疫细胞中以相当高的水平表达，在那里它可能介导甲基苯丙胺对免疫系统的诱导作用，并且在这方面，可能在甲基苯丙胺对人类和猿猴免疫缺陷病毒感染性和疾病进展的相关作用中发挥作用。这种受体在调节脑单胺系统和潜在的免疫细胞功能中的重要性为确定该位点的多态性变异是否具有功能性和检查人与恒河猴之间的显著相似性提供了强有力的理由。在这项资助中，我们应用我们实验室在评估TAAR 1功能，与药物成瘾和神经精神疾病相关的恒河猴基因多态性发现，以及遗传变异功能评估方面的重要专业知识，开始对TAAR 1基因座进行调查。我们将鉴定和评估恒河猴和人类TAAR 1基因座中新的遗传多态性的功能，以确定TAAR 1多态性是否有助于遗传变异性，该遗传变异性是神经精神和药物成瘾障碍以及潜在的甲基苯丙胺的易感性和/或保护的基础。 对免疫系统的影响这是一个全新的领域，没有调查报告，我们的初步数据验证了恒河猴TAAR 1基因座多态性的存在。

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. Rhesus monkey Trace Amine-Associated Receptor 1 (TAAR1) responds to a wide spectrum of endogenous amines (including the "trace" amines betta-phenylethylamine and tyramine, and the common biogenic amines dopamine, norepinephrine and serotonin), as well as amphetamine-like psychostimulants, including methamphetamine. In rhesus monkey brain, we have shown that TAAR1 mRNA is expressed in monoaminergic regions, and that TAAR1 is co-expressed with and modulates monoamine transporters in monoaminergic neurons. Our studies have demonstrated that TAAR1 is activated along with monoamine autoreceptors by the common biogenic amines, but that only TAAR1 is activated by methamphetamine, resulting in aberrant cAMP accumulation, triggering of cellular phosphorylation events and a consequent deregulation of monoamine transporter kinetic function. We have also recently found that TAAR1 is expressed at substantially high levels in rhesus monkey and human immune cells where it may mediate methamphetamine-induced effects on the immune system and in this regard, may play a role in methamphetamine-associated effects on human and simian immunodeficiency virus infectivity and disease progression. The emerging importance of this receptor in modulating brain monoamine systems and potentially immune cell function provides a strong rationale for determining whether polymorphic variation at the locus is functional and examining the significant similarities between human and rhesus monkeys. In this grant we apply our laboratory's significant expertise in assessing TAAR1 function, polymorphism discovery in rhesus monkey genes associated with drug addiction and neuropsychiatric disorders, and genetic variant functional assessments to initiate investigation of the TAAR1 locus. We will identify and assess functionality of the novel genetic polymorphisms in both the rhesus monkey and human TAAR1 locus to determine whether TAAR1 polymorphisms could contribute to the genetic variability that underlies susceptibility to and/or protection from neuropsychiatric and drug addiction disorders, and potentially, methamphetamine effects on the immune system. This is a completely novel area in which no investigations have been reported, and our preliminary data verifies the existence of polymorphisms in the rhesus monkey TAAR1 locus.