My long term career goal is to be an independently-funded primary investigator running a research laboratory focused on psychiatric genetics and the pharmacogenetics of psychiatric disease. My background, however, is in cancer genetics, which was the subject of my graduate research. Although I have now worked on psychiatric genetics for almost two years, I still have much to learn on the subject matter. The K01 award is used by new researchers who need more training before becoming independent, particularly those who are learning a new field. This award will be integral in providing me with the training in neuroscience and psychiatric disease necessary to eventually apply for an R01 award and successfully run my own laboratory. Our laboratory has observed a potentially interesting pharmacogenetic effect in a clinical trial of opioid addiction treatment. Te trial compared the efficacy of methadone and buprenorphine, two FDA-approved opioid addiction medications, by analyzing urine drug screens over 24 weeks. We identified an effect of a genetic variant in OPRD1, the gene encoding the ?-opioid receptor, in African-American patients. Methadone patients carrying the minor allele of the variant had more opioid positive urine tests than those who only carried the major allele. The opposite effect was observed in buprenorphine patients: patients carrying the minor allele had fewer opioid positive urine tests. Confirmation of these findings would have substantial clinical benefit, significantly improving treatment outcome in African-Americans. In this application, we propose to collect an independent confirmatory set of DNA samples from African-Americans being treated with either methadone or buprenorphine for opioid addiction. The entire OPRD1 gene will be sequenced in all samples and variants will be analyzed for associations with treatment outcome. We will also study the effects of the polymorphism of interest on OPRD1 expression in both postmortem brain tissue and neuronal cell lines. In keeping with my stated career plan, the goal of the training included in this proposal is to provide me with the research skills necessary to become an independent researcher in the fields of psychiatric genetics and pharmacogenetics.
Each aim of this proposal is designed to enhance my knowledge in a specific area of psychiatric genetics. The first specific aim will provide an understanding of the clinical environment, including recruitment of eligible patients to the study, explanation of informed consent to patients, and proper handling of human samples and sensitive data.
The second aim will cover the general handling of large data files in the programming language R, which is commonly used in the biological sciences for data analysis, and more specific tasks such as sequence alignment and variant calling using common bioinformatics programs.
The final aim will focus on the functional assessment of OPRD1 variant, using molecular genetics techniques to determine how the variant affects expression and splicing of OPRD1.
Genetic variations in genes encoding opioid receptors have been associated with the risk of developing drug addiction, as well as clinical outcome in addiction treatment programs. This study will examine the role of OPRD1, the gene encoding the d-opioid receptor, in the efficacy of methadone and buprenorphine in opioid addiction treatment.
|Crist, R C; Doyle, G A; Kampman, K M et al. (2016) A delta-opioid receptor genetic variant is associated with abstinence prior to and during cocaine dependence treatment. Drug Alcohol Depend 166:268-71|
|Crist, R C; Doyle, G A; Nelson, E C et al. (2016) A polymorphism in the OPRM1 3'-untranslated region is associated with methadone efficacy in treating opioid dependence. Pharmacogenomics J :|