Pharmacogenomics of Interferon-Induced Depression

描述（由申请人提供）：本次K23申请的候选人是一名精神病学家，希望获得药物基因组学方面的专业知识。他打算通过指导教学、咨询和一项研究方案来实现这一目标，该研究方案旨在检查可能影响人类对干扰素诱导的抑郁症（I-ID）易感性的遗传多态性。干扰素- α可引发约25%的患者抑郁，是丙型肝炎的主要治疗方法，在美国，丙型肝炎影响约400万人。此外，这本身就是一个重要的精神健康问题，I-ID提供了一个可行的机会，可以研究一种潜在的人类抑郁症模型。因此，特定的候选多态性将在具有良好特征的丙型肝炎患者队列中进行检查，这些患者在干扰素a治疗之前进行评估，并且目前处于健康状态。随访抑郁症的发展情况，以及干扰素a暴露的药代动力学评估。结合教学培训，本研究将为获得临床药理学研究中定量遗传学和关联分析方面的专业知识提供一个平台，并设计使用高通量遗传多态性分析。教学培训将包括人类遗传学的特定课程，监督阅读和软件教程，以及接触高通量实验室技术。同时，还将包括一项小型辅助试点研究，以确定I-ID进一步遗传关联分析的潜在候选基因。这项辅助研究将在干扰素- α暴露的类似小鼠模型中产生先导微阵列数据，以确定受干扰素- α影响的全基因组额叶皮质基因集。结合微阵列数据分析和协作验证的教学培训，该辅助项目将提供一个培训平台，将微阵列的使用纳入精神病学药物遗传学研究。这个发展计划将启动候选人的长期跨学科和综合策略来描述抑郁症的遗传易感性。

DESCRIPTION (provided by applicant): 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.