BLRD Research Career Scientist Award Application

项目摘要/摘要 理查兹博士(菲利普斯饰)在她的实验室内领导一个研究小组，由一名高级研究助理组成， 全职实验室技术人员，一名研究生和几名暑期实习生。她还执导着 NIH/NIAAA资助的波特兰酒精研究中心(PARC)，该中心涉及14名研究科学家和他们的 实验室研究人员。帕洛阿尔托研究所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、星形胶质突起和 细胞外基质(ECM)，在长期饮酒的风险和影响。她有一项研究 在帕洛阿尔托气候变化研究项目中的组成部分和资助甲基苯丙胺(MA)研究的赠款。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的风险。基因小鼠 种群对成瘾的各个方面进行建模，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、认知因素和 生理上的关联。最近，她的工作特别强调了具有弹性的个人 遗传风险强，不选择高水平的药物摄入。她认为，对这些人的研究 将提供与治疗发展相关的相反基因和机制的重要信息。 与促进使用的奖励药物作用相比，这些保护作用还没有得到充分的研究。事实上, 人类遗传学研究不包括曾尝试过某种药物并发现它是 厌恶的，因此避免使用它。他们也没有像研究人口那样深入研究个体差异 效果(即，COMMON是非使用者和有使用障碍的群体的比较)。理查兹博士的退伍军人荣誉奖 审查资助的研究重点是狂欢MA的使用和单核苷酸多态在 示踪胺相关受体1基因(Taar1m1J)，由她的实验室发现，占遗传基因的60% 在她选择的品系遗传动物模型中，自愿摄入MA的差异。目标包括识别神经毒性 MA的影响和Taar1变异对这些影响的敏感性；以及遗传鉴定 高风险的修饰物，Taar1m1J/m1J基因，预测高水平的自愿MA摄入量，使用选择性 育种和转录学。她资助的R01赠款被用来培育转基因小鼠，以证明Taar1是 MA摄入量的数量性状基因和其他影响MA摄入量的MA性状，包括索引 对并购奖励和厌恶的敏感性。重组近交系菌株正被用于比较基因网络 全部具有高危Taar1m1J/m1J基因，但表现出不同数量MA的小鼠的结局 入口处。对MU-阿片受体基因(OPRM1)潜在相互作用的靶向评估表明 OPRM1等位基因变异会影响Taar1基因对MA摄入量和其他MA相关性状的影响。Dr。 理查兹在帕洛阿尔托研究所的研究项目是用小鼠研究酒精偏好的风险转录组 有选择地为高或低酒精偏好而饲养。她还进行了一项旨在剖析 通过检测基因与个体差异对遗传风险的反应有关的转录差异 具有不同偏好水平的小鼠的表达网络与高酒精偏好线不同。最后， 她的研究小组正在根据转录组的发现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。

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.