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

描述（由申请人提供）：我的研究重点是药物滥用和神经精神疾病的遗传变异，以及成瘾药物的基本神经生物学机制。在这个奖项下，我将模型组件的人类多巴胺能神经遗传变异的基础药物成瘾，酗酒和神经精神疾病的恒河猴。虽然恒河猴通常具有与人类不同的等位基因，但与已知导致神经精神疾病和成瘾性疾病变异的人类基因相比，该物种的遗传变异具有共同的功能。我将系统地揭示恒河猴血清素转运蛋白（SERT），色氨酸羟化酶2（TPH 2）和单胺氧化酶A（MAOA）基因的功能可比多态性，并评估与药物成瘾，酒精中毒和神经精神疾病相关的基因型/表型关系。通过选择恒河猴，自然窝藏一系列可比的功能等位基因在这些β-肾上腺素能基因，我将研究影响疾病相关表型的遗传相互作用，并开发一个高度翻译的临床前平台，用于开发药物基因组学知情的人类个性化医疗。开发成瘾和精神疾病的新疗法的主题延伸到对脑单胺能系统的调节和痕量胺相关受体1（TAAR 1）的作用的补充研究重点。TAAR 1是单胺类和苯丙胺类药物的主要靶标。在这个奖项下，我将研究TAAR 1在大脑，免疫系统和外周中的作用。我最近对TAAR 1的研究强烈表明，该受体是开发神经精神和成瘾性疾病，特别是甲基苯丙胺成瘾的新疗法的靶点。我将通过分子筛选方法和体外和体内新化合物的评估来追踪这些线索。这两个研究项目都与我提议的TAAR 1基因研究相结合，该基因具有多态性，可能是人类和恒河猴受体功能或表达差异的基础。在这个奖项下，我将从行政，委员会，核心和财团的责任中解脱出来，这样我就可以把更多的时间（>75%）用于进行研究和与我的独立研究生涯的进一步发展直接相关的活动，并指导学员。我还将参加各种培训经验，在负责任的研究行为，并创建一个研讨会上介绍研究伦理，我将提供给我们的研究人员和学生的社区。

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.