The candidate for this K23 application is a psychiatrist who proposes to acquire expertise in pharmacogenomics. He intends to accomplish this goal through guided didactics and consultations and a research protocol designed to examine genetic polymorphisms that may affect vulnerability to interferon-alpha-induced depression (I-ID) in humans. Interferon-alpha can trigger depression in about 25% of patients and is the primary treatment for hepatitis C, which affects about 4 million individuals in the U.S. In addition to this being a significant mental health issue in its own right, I-ID offers the opportunity to feasibly examine a prospective human model of depression. Therefore, specific candidate polymorphisms will be examined in a well-characterized cohort of patients with hepatitis C who are assessed prior to interferon-a treatment and who are currently euthymic. The development of depression will be prospectively followed, along with pharmacokinetic assessments of interferon-a exposure. In conjunction with didactic training, this research will provide a platform for acquiring expertise in quantitative genetics and associational analyses in clinical pharmacology research, and designs using high throughput genetic polymorphism assays. The didactic training will involve specific classes in human genetics, supervised readings and software tutorials, and exposure to high throughput laboratory techniques. A small ancillary pilot study will also be included to ascertain, in parallel, potential candidate genes for further genetic association analyses of I-ID. This ancillary study will generate pilot micro-array data in an analogous murine model of interferon-alpha exposure, ascertaining the genome-wide set of frontal cortical genes affected by interferon-alpha. In conjunction with didactic training in the analysis and collaborative verification of micro-array data, this ancillary project will provide a training platform for incorporating the use of micro-arrays into psychiatric pharmacogenetic research. This developmental program will initiate the candidate's long-term interdisciplinary and integrative strategy for delineating genetic vulnerability to depression.
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