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.

项目总结/摘要 博士理查兹（菲利普斯）在她的实验室里领导一个研究小组，包括一名高级研究助理， 全职实验室技术人员，一名研究生和几名暑期实习生。她还指导了 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团队。 实验室研究人员。PARC正在努力实现共同的目标，即调查 四分突触，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），在风险和慢性饮酒的影响。她有一项研究 PARC的组成部分，并资助甲基苯丙胺（MA）研究。总体而言，她 实验室开发和利用专门的遗传小鼠种群，目的是了解 成瘾风险的多方面病因和确定个性化治疗。基因小鼠 群体模拟成瘾的各个方面，然后对转录组进行深入研究， 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，包括药物刺激效应、奖励、强化、厌恶、回避、认知因素，以及 生理相关最近，她的工作特别强调有弹性的个人， 强烈的遗传风险，不选择高水平的药物摄入。她认为对这些人的研究 将提供重要的信息，反对基因和机制有关的治疗发展。 与促进使用的奖励药物作用相比，这些保护作用未得到充分研究。事实上， 人类遗传学研究不包括那些用药物进行实验并发现它是 因此避免使用。他们也没有像研究人口那样深入研究个体差异 效果（即，常见的是将非吸毒者与吸毒障碍群体进行比较）。理查兹博士，VA Merit 审查资助的研究集中在MA的狂欢使用和单核苷酸多态性的影响， 微量胺相关受体1基因（Taar 1 m1 J），由她的实验室发现，占60%的遗传 在她选择的品系遗传动物模型中自愿MA摄入量的方差。目的包括识别神经毒性 MA的影响和Taar 1变异在对这些影响敏感性中的作用;以及鉴定遗传 高风险的修饰符，Taar 1 m1 J/m1 J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R 01基金被用来产生敲入小鼠，以证明Taar 1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，包括指示 对MA奖励和厌恶的敏感性。重组近交系被用来比较基因网络 所有具有高风险Taar 1 m1 J/m1 J基因型但表现出不同数量MA的小鼠的结果 摄入对μ阿片受体基因（Oprm 1）潜在相互作用的靶向评估表明， Oprm 1等位基因变异影响Taar 1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是用老鼠研究酒精偏好的风险转录组 有选择性地培育高或低酒精偏好。她还在进行一项研究， 转录差异与个体变异响应遗传风险，通过检查基因 表达网络在小鼠与高酒精偏好线的不同偏好水平。最后， 她的研究小组正在进行基于转录组发现的治疗相关研究，探索新的 酒精使用障碍的药物治疗途径。