Drug Abuse-related Neurobiology and Genetic Variance Modeled in Rhesus Monkeys

描述(申请人提供)：我的研究重点是物质滥用和神经精神障碍背后的遗传变异，以及成瘾药物的基本神经生物学机制。根据这一奖项，我将对恒河猴的药物成瘾、酒精中毒和神经精神障碍的人类5-羟色胺能神经遗传变异的组成部分进行建模。尽管恒河猴的等位基因通常与人类不同，但与已知导致神经精神疾病和成瘾性疾病差异的同源人类基因相比，这一物种的基因变异具有共同的功能。我将系统地发现恒河猴5-羟色胺转运体(SERT)、色氨酸羟化酶2(TPH2)和单胺氧化酶A(MAOA)基因在功能上具有可比性的多态，并评估与药物成瘾、酒精中毒和神经精神障碍相关的基因/表型关系。通过选择在这些5-羟色胺能基因中自然含有一系列可比功能等位基因的恒河猴，我将研究影响疾病相关表型的遗传交互作用，并为药物基因组信息的人类个性化药物开发开发一个高度翻译的临床前平台。开发治疗成瘾和精神障碍的新疗法的主题延伸到对大脑单胺能系统的调节和痕量胺相关受体1(TAAR1)的作用的补充研究。TAAR1是单胺和苯丙胺类药物的主要靶点。在这个奖项下，我将研究TAAR1在大脑、免疫系统和外周的作用。我最近对TAAR1的研究有力地表明，该受体是开发治疗神经精神和成瘾障碍的新疗法的目标，特别是治疗甲基苯丙胺成瘾。我将通过分子筛选方法和通过在体外和体内对新化合物的评估来寻找这些线索。这两个研究项目都与我提出的对TAAR1基因的研究相结合，该基因的多态可能是人类和恒河猴受体功能或表达差异的基础。根据这个奖项，我将从行政、委员会、核心和财团的责任中解脱出来，这样我就可以有更多的时间(75%)进行研究，从事与我的独立研究事业的进一步发展和对学员的指导直接相关的活动。我还将参加各种负责任的研究行为的培训经验，并创建一个关于研究道德的研讨会演示文稿，我将向我们的研究人员和学生社区发表演讲。与公共卫生相关：恒河猴与人类在遗传和生理上有密切的相似之处，这是平行的行为、发育、生理和代谢活动的基础。这项拟议的研究确定了恒河猴基因的遗传变异，这些基因变异自然地模拟了人类潜在的神经精神和成瘾障碍变异的功能，并模拟了与基本神经生物学机制和滥用药物的药物基因组学相关的基因/表型关系。

DESCRIPTION (provided by applicant): My research focuses on the genetic variance that underlies substance abuse and neuropsychiatric disorders, and also the basic neurobiological mechanisms of addictive drugs. Under this award, I will model components of human serotonergic neurogenetic variance underlying drug addiction, alcoholism and neuropsychiatric disorders in rhesus monkeys. Though rhesus monkeys often harbor different alleles than occur in humans, genetic variants in this species have common functionality compared with those in orthologous human genes known to contribute to the variance of neuropsychiatric and addictive disease. I will systematically uncover functionally comparable polymorphisms in rhesus monkey serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) genes, and assess genotype/phenotype relationships relevant to drug addiction, alcoholism and neuropsychiatric disorders. By selecting rhesus monkeys that naturally harbor an array of comparable functional alleles in these serotonergic genes, I will study genetic interactions influencing disorder-related phenotypes and develop a highly translational preclinical platform for the development of pharmacogenomic-informed human personalized medicine. The theme of developing novel therapeutics for addiction and psychiatric disorders extends to a complimentary research focus on the regulation of brain monoaminergic systems and the role of Trace Amine Associated Receptor 1 (TAAR1). TAAR1 is a primary target of monoamines and amphetamine like drugs. Under this award, I will study the role of TAAR1 in brain, the immune system, and the periphery. My recent work on TAAR1 strongly suggests that the receptor is a target for the development of novel therapeutics for neuropsychiatric and addiction disorders and particularly, for methamphetamine addiction. I will pursue these leads through a molecular screening approach and through assessment of novel compounds in vitro and in vivo. Both research programs join with my proposed study of the TAAR1 gene, which has polymorphisms that may underlie differences in receptor function or expression in both humans and rhesus monkeys. Under this award, I will be freed from administrative, committee, core and consortium responsibilities, so that I can devote more time (>75%) to conducting research and to activities that are directly related to the further development of my independent research career and mentoring of trainees. I will also participate in a variety of training experiences in the responsible conduct of research, and create a seminar presentation on research ethics that I will deliver to our community of researchers and students. PUBLIC HEALTH RELEVANCE: Rhesus monkeys have close genetic and physiological similarities with humans that underlie parallel behavioral, developmental, physiological, and metabolic activities. The proposed research identifies genetic variations in rhesus monkey genes that naturally mimick the function of those underlying neuropsychiatric and addictive disorder variance in humans, and models genotype/phenotype relationships relevant to basic neurobiological mechanisms and the pharmacogenomics of drugs of abuse.