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.

项目摘要/摘要 理查兹（Richards）博士（菲利普斯（Phillips））指导她的实验室中的一个研究小组，包括一名高级研究助理， 专职实验室技术人员，研究生和几个暑期实习生。她还指导 NIH/NIAAA资助的波特兰酒精研究中心（PARC），涉及14位研究科学家及其 实验室研究人员。 PARC正在朝着研究调查角色的共同目标 四方突触，包括前后突触后神经元，星形胶质过程以及 细胞外基质（ECM）有慢性酒精饮用的风险和影响。她有一项研究 PARC中的组成部分和资助的赠款支持甲基苯丙胺（MA）研究。总的来说，她 实验室发展并利用专门的遗传小鼠种群，目的是理解 成瘾风险和识别个性化治疗的多方面病因。遗传小鼠 种群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。她研究多种灵敏度 因素，包括药物刺激作用，奖励，加强，厌恶，回避，认知因素和 生理相关。最近，她的工作特别强调了 强烈的遗传风险不会选择高水平的药物摄入。她认为对这些人的研究 将提供有关与治疗发展相关的相对基因和机制的重要信息。 与促进使用的奖励药物效应相比，这些保护作用被研究了。实际上， 人类遗传研究不包括已经尝试过药物的个体并发现它是 厌恶，因此避免使用。他们也没有像人口一样深入研究个体差异 效果（即，常见是对使用障碍的非用户和群体的比较）。理查兹博士的VA功绩 审查资助的研究集中于暴饮暴食和单个核苷酸多态性在 痕量胺相关受体1基因（TAAR1M1J），她的实验室发现，占遗传的60％ 她选定的线遗传动物模型中自愿摄入的差异。目的包括识别神经毒性 MA的影响以及TAAR1变异在对这些影响敏感性中的作用；和遗传的鉴定 高风险的修饰符，TAAR1M1J/M1J基因型，可预测高水平的自愿MA摄入量，使用选择性 繁殖和转录组学。她资助的R01赠款用于生成敲入鼠标，以证明Taar1是 用于MA摄入量的定量特征基因和影响MA摄入的其他MA性状，包括索引的特征 对MA奖励和厌恶的敏感性。重组近交菌株被用于比较基因网络 在小鼠中，所有人都具有高风险TAAR1M1J/M1J基因型，但表现出不同的MA 进气。针对MU-阿片受体基因（OPRM1）的潜在相互作用的有针对性评估表明 OPRM1等位基因变异会影响TAAR1基因型对MA摄入和其他MA相关性状的影响。博士 理查兹（Richards）在PARC中的研究项目正在研究使用小鼠的酒精偏好的风险转录组 有选择地育种，以高或低酒精的偏好。她还在进行旨在剖析的研究 通过检查基因，转录差异与遗传风险相关的个体变异有关 与高酒精偏好系的偏好水平不同的小鼠的表达网络。最后， 她的研究小组正在根据转录组发现进行与治疗相关的研究，并探索新的 酒精使用障碍的药物治疗途径。