BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10696821
• 负责人: TAMARA J. RICHARDS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2030-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696821
• 关键词: ARHGEF5 gene; Abstinence; Accounting; Alcohol dependence; Alcohols; Alleles; Amines; Animal Genetics; Animal Model; Award; Behavioral Mechanisms; Biological Markers; Brain; Breeding; CRISPR/Cas technology; Candidate Disease Gene; Chromosome 10; Chronic; Cognitive; Collaborations; Combined Modality Therapy; Consumption; Data; Disease; Drug Addiction; Drug Controls; Drug usage; Epigenetic Process; Etiology; Exhibits; Extracellular Matrix; Family; Funding; Gene Expression; Genes; Genetic; Genetic Models; Genetic Risk; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Goals; Grant; Health; Human; Human Genetics; Incentives; Individual; Individual Differences; Institution; Intake; Intervention; Investigation; Knock-in Mouse; Laboratories; Laboratory Research; Laboratory Technicians; Medical; Mental disorders; Methamphetamine; Military Personnel; Modality; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Opioid; Outcome; Pathway Analysis; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Physiological; Population; Population Genetics; Postdoctoral Fellow; Process; Psychiatry; Psychological reinforcement; Publications; Quantitative Genetics; Receptor Gene; Recombinant Inbred Strain; Reporting; Research; Research Design; Research Personnel; Research Project Grants; Rewards; Risk; Risk Factors; Role; Scientist; Sex Differences; Single Nucleotide Polymorphism; Stimulant; Synapses; Toxic effect; United States National Institutes of Health; Variant; Veterans; Work; addiction; alcohol misuse; alcohol research; alcohol use disorder; career; chronic alcohol ingestion; contingency management; craving; differential expression; drug reward; early experience; evidence base; gene network; genetic risk factor; graduate student; high risk; human model; indexing; individual variation; individualized medicine; methamphetamine abuse; methamphetamine effect; methamphetamine use; mouse model; mu opioid receptors; neuromechanism; neuropsychiatric disorder; neuropsychopharmacology; neurotoxic; personalized medicine; pharmacologic; postsynaptic neurons; preference; presynaptic neurons; programs; protective effect; psychologic; psychosocial; receptor; resilience; response; substance use; summer internship; therapeutic development; therapy development; trait; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract Dr. Richards (Phillips) directs a research group within her laboratory, comprising a Senior Research Associate, full-time laboratory technicians, a graduate student, and several summer interns. She also directs the NIH/NIAAA-funded Portland Alcohol Research Center (PARC), which involves 14 research scientists and their laboratory research personnel. The PARC is working toward the common goal of investigating the role of the tetrapartite synapse, with components including the pre- and post-synaptic neuron, astroglial processes, and the extracellular matrix (ECM), in risk for and the impact of chronic alcohol drinking. She has a research component in the PARC and funded grants supporting methamphetamine (MA) research. Overall, her laboratory develops and utilizes specialized genetic mouse populations, with the goal of understanding multifaceted etiologies of risk for addiction and of identifying personalized treatments. The genetic mouse populations model various aspects of addiction and are then subjected to in-depth study of the transcriptome, single gene effects, genetically correlated behaviors and neural mechanisms. She studies multiple sensitivity factors, including drug stimulant effects, reward, reinforcement, aversion, avoidance, cognitive factors, and physiological correlates. Most recently, her work has placed a particular emphasis on resilient individuals with strong genetic risk that do not choose high levels of drug intake. She believes that study of these individuals will provide important information about opposing genes and mechanisms relevant to therapeutic development. These protective effects are understudied in comparison to use-promoting rewarding drug effects. In fact, human genetic studies do not include individuals who have experimented with a drug and found it to be aversive, therefore avoiding its use. Nor have they delved into individual differences as much as population effects (i.e., common is comparison of non-users and groups with use disorders). Dr. Richards' VA Merit Review-funded research is focused on binge MA use and the impact of a single nucleotide polymorphism in the trace amine-associated receptor 1 gene (Taar1m1J), discovered by her lab to account for 60% of the genetic variance in voluntary MA intake in her selected line genetic animal model. Aims include identifying neurotoxic effects of MA and the role of Taar1 variation in sensitivity to those effects; and identification of genetic modifiers of the high risk, Taar1m1J/m1J genotype that predicts high levels of voluntary MA intake, using selective breeding and transcriptomics. Her funded R01 grant was used to generate knock-in mice to prove that Taar1 is a quantitative trait gene for MA intake and other MA traits that impact MA intake, including traits that index sensitivity to MA reward and aversion. Recombinant inbred strains are being used to compare gene network outcomes in mice that all possess the high risk Taar1m1J/m1J genotype, but exhibit different amounts of MA intake. Targeted assessment of a potential interactive effect of the mu-opioid receptor gene (Oprm1) indicate that Oprm1 allelic variation impacts the effect of Taar1 genotype on MA intake and other MA-related traits. Dr. Richards' research project within the PARC is studying the risk transcriptome for alcohol preference using mice selectively bred for high or low alcohol preference. She is also performing research designed to dissect transcriptional differences associated with individual variation in response to genetic risk, by examining gene expression networks in mice with differential levels of preference from the high alcohol preference line. Finally, her research group is performing treatment-related research based on transcriptome findings, exploring new pharmacotherapeutic avenues for alcohol use disorder.

项目概要/摘要 理查兹博士（菲利普斯）在她的实验室内领导一个研究小组，包括一名高级研究员、 全职实验室技术人员、一名研究生和多名暑期实习生。她还执导 NIH/NIAAA 资助的波特兰酒精研究中心 (PARC)，包括 14 名研究科学家和他们的研究人员 实验室研究人员。 PARC 正在努力实现调查 PARC 的作用的共同目标。 四部分突触，其组成部分包括突触前和突触后神经元、星形胶质细胞突起和 细胞外基质（ECM），存在长期饮酒的风险和影响。她有一项研究 PARC 的组成部分，并为支持甲基苯丙胺 (MA) 研究提供资助。总的来说，她 实验室开发和利用专门的基因小鼠群体，目的是了解 成瘾风险和确定个性化治疗的多方面病因。基因小鼠 人群对成瘾的各个方面进行建模，然后进行转录组的深入研究， 单基因效应、遗传相关行为和神经机制。她研究多重敏感性 因素，包括药物刺激作用、奖励、强化、厌恶、回避、认知因素，以及 生理相关性。最近，她的工作特别强调具有韧性的个人 遗传风险强的人不要选择高水平的药物摄入。她认为对这些人的研究 将提供有关与治疗开发相关的相反基因和机制的重要信息。 与促进使用的奖励性药物作用相比，这些保护作用尚未得到充分研究。实际上， 人类基因研究不包括尝试过某种药物并发现该药物有效的个体 厌恶，因此避免使用它。他们也没有像人口那样深入研究个体差异 效果（即，常见的是非使用者和有使用障碍的群体的比较）。理查兹博士的 VA 优点 审查资助的研究重点是 MA 的大量使用以及单核苷酸多态性对 她的实验室发现微量胺相关受体 1 基因 (Taar1m1J) 占遗传基因的 60% 她选择的系遗传动物模型中自愿摄入 MA 的差异。目标包括识别神经毒性物质 MA 的影响以及 Taar1 变异在对这些影响的敏感性中的作用；和遗传鉴定 高风险的修饰因子，Taar1m1J/m1J 基因型，预测高水平的自愿 MA 摄入量，使用选择性 育种和转录组学。她资助的 R01 资金用于生成基因敲入小鼠，以证明 Taar1 是 MA 摄入量的数量性状基因和影响 MA 摄入量的其他 MA 性状，包括索引的性状 对 MA 奖励和厌恶的敏感性。重组近交系用于比较基因网络 具有高风险 Taar1m1J/m1J 基因型但表现出不同量 MA 的小鼠的结果 摄入量。对 mu-阿片受体基因 (Oprm1) 潜在相互作用效应的针对性评估表明 Oprm1 等位基因变异影响 Taar1 基因型对 MA 摄入量和其他 MA 相关性状的影响。博士。 理查兹在帕洛阿尔托研究中心的研究项目正在使用小鼠研究酒精偏好的风险转录组 根据高酒精度或低酒精度偏好进行选择性培育。她还在进行旨在剖析的研究 通过检查基因，发现与个体差异相关的转录差异，以应对遗传风险 与高酒精偏好系具有不同偏好水平的小鼠的表达网络。最后， 她的研究小组正在根据转录组研究结果进行与治疗相关的研究，探索新的 酒精使用障碍的药物治疗途径。