TAAR1 polymorphisms in rhesus monkeys

描述(申请人提供)：恒河猴痕量胺相关受体1(TAAR1)对多种内源性胺(包括微量胺2-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)以及苯丙胺类精神刺激剂(包括甲基苯丙胺)都有反应。在恒河猴脑中，TAAR1mRNA在单胺能区表达，TAAR1与单胺能神经元共表达并调控单胺转运体。我们的研究表明，TAAR1与单胺自身受体一起被常见的生物胺激活，但只有TAAR1被甲基苯丙胺激活，导致cAMP异常积累，触发细胞磷酸化事件，从而解除对单胺转运体动力学功能的调控。我们最近还发现，TAAR1在恒河猴和人类免疫细胞中的表达水平相当高，它可能介导了甲基苯丙胺对免疫系统的影响，并在这方面可能在甲基苯丙胺对人类和猿类免疫缺陷病毒感染性和疾病进展的影响中发挥作用。这种受体在调节大脑单胺系统和潜在的免疫细胞功能方面的重要性正在显现，这为确定该基因的多态变异是否具有功能性并研究人类和恒河猴之间的显著相似性提供了强有力的理论基础。在这笔赠款中，我们应用我们实验室在评估TAAR1功能、与药物成瘾和神经精神障碍相关的恒河猴基因多态发现以及遗传变异功能评估方面的重要专业知识，启动对TAAR1基因座的调查。我们将在恒河猴和人类的TAAR1基因座上鉴定和评估新的遗传多态的功能，以确定TAAR1多态是否有助于遗传多样性，这种遗传多样性是神经精神和药物成瘾疾病的易感性和/或保护基础，也是潜在的甲基苯丙胺对免疫系统的影响。这是一个全新的领域，没有任何研究报道，我们的初步数据证实了恒河猴TAAR1基因座存在多态。公共卫生相关性：在这笔赠款中，我们应用我们实验室在评估痕量胺相关受体1(TAAR1)功能和识别与药物成瘾和神经精神疾病相关的新基因多态方面的重要专业知识，启动了对恒河猴和人类TAAR1基因座的研究。这种受体在调节大脑单胺系统和潜在的免疫细胞功能方面的重要性正在显现，这为确定多态变异是否具有功能性以及研究人类和恒河猴之间的相似性提供了强有力的理论基础。

DESCRIPTION (provided by applicant): Rhesus monkey Trace Amine-Associated Receptor 1 (TAAR1) responds to a wide spectrum of endogenous amines (including the "trace" amines 2-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. PUBLIC HEALTH RELEVANCE: In this grant, we apply our laboratory's significant expertise in assessing the function of Trace Amine Associated receptor 1 (TAAR1) and identifying novel polymorphisms in rhesus monkey genes associated with drug addiction and neuropsychiatric disorders to initiate investigation of the rhesus monkey and human TAAR1 locus. 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 is functional, and examining the similarities between human and rhesus monkeys.