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，我将在恒河猴身上模拟人类血清素能神经遗传变异的组成部分，这些变异是药物成瘾，酒精中毒和神经精神疾病的基础。尽管恒河猴经常携带与人类不同的等位基因，但与已知导致神经精神和成瘾疾病变异的人类同源基因相比，恒河猴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体（SERT）、色氨酸羟化酶2 （TPH2）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。通过选择在这些血清素能基因中天然含有一系列可比较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相互作用，并为药物基因组学信息的人类个性化医疗开发一个高度可转化的临床前平台。开发成瘾和精神疾病的新疗法的主题扩展到对脑单胺能系统的调节和微量胺相关受体1 （TAAR1）的作用的补充研究。TAAR1是单胺类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、免疫系统和外周中的作用。我最近对TAAR1的研究强烈表明，该受体是开发神经精神和成瘾障碍，特别是甲基苯丙胺成瘾的新疗法的目标。我将通过分子筛选方法和通过体外和体内新化合物的评估来追求这些线索。这两个研究项目都与我提出的TAAR1基因研究相结合，TAAR1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%）用于进行研究以及与我独立研究生涯的进一步发展直接相关的活动和指导学员。我还将参加各种关于负责任的研究行为的培训经验，并创建一个关于研究伦理的研讨会报告，我将向我们的研究人员和学生社区提供。公共卫生相关性：恒河猴与人类具有密切的遗传和生理相似性，这是平行行为、发育、生理和代谢活动的基础。该研究确定了恒河猴基因的遗传变异，这些基因自然地模仿了人类潜在的神经精神和成瘾障碍变异的功能，并建立了与基本神经生物学机制和药物基因组学相关的基因型/表型关系模型。

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.