GENE-EXPRESSION CHANGE AND ANTI-DEPRESSANT RESPONSE

描述（由申请人提供）：该项目的目标是开发可用于帮助诊断和治疗抑郁症的分子工具。目前用于治疗抑郁症的药物只有大约50%的时间有效，而且很少有客观的措施可以预测对特定治疗的反应。因此，分子探针的可用性可以指导治疗的初始选择和/或在分子水平上监测对治疗的反应（可能在临床反应前几周发生），这将为抑郁症的治疗提供巨大的进步。我们将采访重度抑郁症患者和非抑郁症对照者，并从他们身上抽血。我们将从血液中提取RNA，并进行微阵列分析，以测量抗抑郁治疗后大量基因表达的变化，以及这些基因表达水平的差异，这些基因在治疗前可能存在于受影响的个体中。这个项目建立在我们之前的工作基础上，研究转基因小鼠和抗抑郁动物的基因表达变化，并将使我们能够将这些研究扩展到临床环境。它涉及到由Ronald Duman博士领导的分子精神病学部门的基础科学研究人员和三个耶鲁附属诊所的临床研究人员之间的合作：耶鲁抑郁症研究诊所、耶鲁行为妇科诊所和VA-CT神经精神病学诊所。这些诊所每年为500多名患者提供服务，包括来自各种种族和社会经济群体的男性和女性。该项目将补充由美国国立卫生研究院计划项目“主要精神疾病的神经生物学”资助的分子精神病学部门正在进行的工作。正在进行的研究使用微阵列分析来检测抗抑郁药物治疗的动物大脑中的基因表达变化以及患有重度抑郁症的人类受试者的死后组织，这将使我们能够将本研究中观察到的任何变化与动物和人类大脑中发生的变化联系起来。

DESCRIPTION (provided by applicant): The goal of this project is to develop molecular tools that can be used to aid in the diagnosis and treatment of depression. Medications currently used to treat depression are only effective approximately 50% of the time and few, if any, objective measures exist, which predict response to a given treatment. Thus, the availability of molecular probes to guide the initial choice of treatment and/or to monitor response to treatment at the molecular level (which may occur weeks in advance of clinical response) would offer an enormous advance in the treatment of depression. We will interview, and draw blood from, individuals with Major Depressive Disorder as well as non-depressed control subjects. We will extract RNA from the blood and perform microarray analysis to measure changes in the expression of a large number of genes in response to anti-depressant treatment, as well as differences in the level of expression of these genes, which may be present in affected individuals prior to treatment. This project builds on our previous work looking at gene-expression changes in transgenic mice and animals treated with anti-depressants and will allow us to expand those studies to a clinical setting. It involves a collaboration between basic science researchers in the Division of Molecular Psychiatry, headed by Dr. Ronald Duman, and clinical researchers at three Yaleaffiliated clinics: the Yale Depression Research Clinic, Yale Behavioral Gynecology Clinic, and the VA-CT Neuropsychiatry Clinic. These clinics serve over five hundred patients each year, and include both men and women from a wide variety of ethnic and socio-economic groups. This project will complement ongoing work in the Division of Molecular Psychiatry funded by our NIH Program Project Grant "The Neurobiology of Major Psychiatric Disorders". Ongoing studies using microarray analysis to detect gene-expression changes in the brains of animals treated with anti-depressants and in post-mortem tissue from human subjects with major depressive disorder will enable us to correlate any changes observed in the present study with those occurring in both animal and human brains. Results from these studies should lead to an RO1 proposal aimed at extending these findings. Briefly, further studies would involve examening differences among different types of depressive disorders and the correlation between gene-expression changes and treatment-response.