权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8472464
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
项目类别：
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/8472464
关键词：
3&apos Untranslated Regions 5&apos Flanking Region Alcohol consumption Alcoholism Alleles Amines Amphetamines Award B-Lymphocytes Behavioral Biological Assay Blood Platelets Brain Cell Line Code Cognitive Communities Detection Development Disease Drug Addiction Drug abuse Genes Genetic Genetic Polymorphism Genetic Variation Genotype Haplotypes Health Human Human Genetics Immune system In Vitro Macaca mulatta Medicine Mental disorders Mentors Metabolic Methamphetamine dependence Modeling Molecular Monoamine Oxidase A Neurobiology Pharmaceutical Preparations Pharmacogenomics Phenotype Physiological Promoter Regions Regulation Research Research Ethics Research Personnel Role Students Substance abuse problem System Testing Time Training Tryptophan 5-monooxygenase Variant Work addiction career drinking behavior drug of abuse experience genetic variant in vivo mRNA Expression monoamine neurobiological mechanism neurogenetics neuropsychiatry novel novel therapeutics pre-clinical programs promoter receptor receptor expression receptor function responsible research conduct screening serotonin transporter

项目摘要

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.

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。根据这个奖项，我将在恒河猴中模拟吸毒、酗酒和神经精神疾病背后的人类血清素神经遗传变异的组成部分。尽管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和成瘾疾病变异的直系同源人类基因相比，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 (TPH2) 和单胺氧化酶 A (MAOA) 基因中功能相似的多态性，并评估与药物成瘾、酗酒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类似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，并开发一个高度转化的临床前平台，用于开发基于药物基因组学的人类个性化医疗。开发针对成瘾和精神疾病的新型疗法的主题延伸到对大脑单胺能系统的调节和微量胺相关受体 1 (TAAR1) 的作用的补充研究重点。 TAAR1 是单胺类药物和苯丙胺类药物的主要靶标。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疾病（尤其是甲基苯丙胺成瘾）新型疗法的目标。我将通过分子筛选方法以及体外和体内新型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 TAAR1 基因研究相结合，该基因的多态性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，我将摆脱行政、委员会、核心和联盟的职责，这样我就可以投入更多的时间（>75%）来进行研究以及与我的独立研究生涯的进一步发展和培训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培训，并制作一个关于研究伦理的研讨会演示文稿，并将其提供给我们的研究人员和学生社区。