BLRD Research Career Scientist Award Application

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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.