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

在恒河猴中建模的药物滥用相关神经生物学和遗传变异

• 批准号: 7893244
• 负责人: GREGORY MICHAEL MILLER
• 金额: $ 12.31万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893244
• 关键词: Alcoholism; Alleles; Amines; Amphetamines; Award; Behavioral; Brain; Cataloging; Catalogs; Communities; Development; Disease; Drug Addiction; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Human; Human Genetics; Immune system; In Vitro; Macaca mulatta; Measurable; Medicine; Mental disorders; Mentors; Metabolic; Methamphetamine dependence; Modeling; Molecular; Monoamine Oxidase A; Neurobiology; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physiological; Recording of previous events; Regulation; Research; Research Ethics; Research Personnel; Role; Screening procedure; Side; Students; Substance abuse problem; System; Time; Training; Tryptophan 5-monooxygenase; Variant; Work; addiction; career; drug of abuse; experience; genetic variant; in vivo; monoamine; neurobiological mechanism; neurogenetics; neuropsychiatry; novel; novel therapeutics; pre-clinical; programs; public health relevance; receptor; receptor function; responsible research conduct; serotonin transporter; trait

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.

描述（由申请人提供）：我的研究重点是基于滥用药物和神经精神疾病的遗传差异，以及成瘾性药物的基本神经生物学机制。根据该奖项，我将对恒河猴中的药物成瘾，酒精中毒和神经精神疾病的人类血清素能神经遗传学方差的成分进行建模。尽管恒河猴通常具有与人类中不同的等位基因不同的等位基因，但与已知有助于神经精神疾病和成瘾性疾病的差异的直系同源人类基因相比，该物种中的遗传变异具有共同的功能。我将在恒河猴5-羟色胺转运蛋白（SERT），色氨酸羟基酶2（TPH2）和单胺氧化酶A（MAOA）基因（MAOA）基因中系统地发现功能可比的多态性，并评估与药物成瘾，酒精中毒和神经精神上的基因型/表型关系。通过选择自然具有这些血清素能基因中一系列可比功能等位基因的恒河猴，我将研究影响与疾病有关的表型的遗传相互作用，并开发出高度转化的临床前平台，用于开发药物基因组知识的人类个性化药物。开发成瘾和精神疾病的新型治疗剂的主题扩展到免费研究的重点，重点是调节脑单胺能系统和痕量胺相关受体1（TAAR1）的作用。 TAAR1是单胺和苯丙胺等药物的主要靶标。根据该奖项，我将研究TAAR1在大脑，免疫系统和外围的作用。我最近在TAAR1上的工作强烈表明，该受体是开发用于神经精神和成瘾疾病的新型治疗剂的靶标，尤其是甲基苯丙胺成瘾的靶标。我将通过分子筛选方法以及评估体外和体内的新化合物来追求这些潜在客户。这两种研究计划都与我对TAAR1基因的拟议研究相结合，该研究的多态性可能是人类和恒河猴的受体功能或表达差异的基础。根据该奖项，我将摆脱行政，委员会，核心和财团的职责，以便我可以花更多的时间（> 75％）进行研究和与我的独立研究职业和学员的进一步发展直接相关的活动。我还将参加负责任的研究进行各种培训经验，并创建有关研究伦理的研讨会介绍，我将向我们的研究人员和学生社区交付。 公共卫生的相关性：恒河猴与人类具有平行行为，发育，生理和代谢活动的人类的遗传和生理相似性。拟议的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中潜在的神经精神疾病和成瘾性疾病差异的人的功能，并模型与基本神经生物学机制和滥用药物药物的基因型/表型关系模型。