TAAR1 POLYMORPHISMS IN RHESUS MONKEYS

恒河猴中的 TAAR1 多态性

• 批准号: 8172884
• 负责人: GREGORY MICHAEL MILLER
• 金额: $ 1.81万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172884
• 关键词: Amines; Amphetamines; Area; Autoreceptors; Biogenic Amines; Brain; Cell physiology; Cells; Computer Retrieval of Information on Scientific Projects Database; Cyclic AMP; Data; Disease; Disease Progression; Dopamine; Drug Addiction; Event; Funding; Genes; Genetic; Genetic Polymorphism; Grant; Human; Immune; Immune system; Institution; Investigation; Kinetics; Laboratories; Macaca mulatta; Mediating; Messenger RNA; Methamphetamine; Neurons; Norepinephrine; Phenethylamines; Phosphorylation; Play; Predisposition; Reporting; Research; Research Personnel; Resources; Role; Serotonin; Source; System; Tyramine; United States National Institutes of Health; Variant; genetic variant; monoamine; neuropsychiatry; novel; psychostimulant; receptor; simian human immunodeficiency virus

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 恒河猴跟踪胺相关的受体1（TAAR1）对多种内源胺反应（包括“痕量”胺贝塔贝塔 - 苯基甲基甲胺和酪氨酸，以及常见的生物胺多巴胺，去甲肾上腺素和呼吸胺） 包括甲基苯丙胺。在恒河猴的大脑中，我们表明TAAR1 mRNA在单胺能区域表达，并且TAAR1与单胺能神经元中的单胺转运蛋白共表达并调节。我们的研究表明，taar1与普通生物胺一起激活了单胺自身受体，但只有TAAR1被甲基苯丙胺激活， 导致cAMP的积累异常，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。我们最近还发现，在恒河猴和人类免疫细胞中，TAAR1在基本上表达，可以介导甲基苯丙胺诱导的对免疫系统的作用，在这方面，可能对甲基苯丙胺相关的人类和邻胺免疫缺陷病毒感染和疾病的影响起着作用。该受体在调节脑单胺系统和潜在的免疫细胞功能中的新兴重要性为确定基因座的多态性变异是否功能性，并检查了人类和恒河猴之间的显着相似性。在这笔赠款中，我们将实验室的重要专业知识应用于评估TAAR1功能，与药物成瘾和神经精神疾病相关的恒河猴基因中的多态性发现以及遗传变异功能评估以启动TAAR1基因座的研究。我们将识别和评估恒河猴和人TAAR1基因座中新型遗传多态性的功能，以确定TAAR1多态性是否可以促进对神经精神上和药物成瘾疾病以及潜在的，甲基甲基胺的易感性和保护性易感性和保护性的遗传变异性。 对免疫系统的影响。这是一个完全新颖的领域，在其中尚未报道研究，我们的初步数据验证了恒河猴TAAR1基因座中多态性的存在。