Profiling Gene Expression in Major Depression

描述（由申请人提供）：脑成像研究报告称，重度抑郁症（MDD）患者的海马体积减少。此外，临床前研究表明，压力降低神经营养因子的表达，减少成年神经发生，并导致海马神经元萎缩。相反，我们实验室和其他研究表明，慢性抗抑郁治疗（ADT）增加了神经营养因子的表达，并增加了海马中的成年神经发生。总之，这些发现有助于抑郁症的神经营养假说。虽然这些临床前结果很有趣，但缺乏关于其在MDD病理生理学和治疗中的临床相关性的信息。当前应用的焦点是使用微阵列分析来鉴定海马体积减少的分子决定因素。为了实现这一目标，我们将使用我们开发的自定义神经营养因子基因芯片来表征抑郁症患者海马亚区的基因表达谱。此外，我们还将使用人类全基因组商业微阵列来识别MDD中改变的其他类型基因。将使用来自匹配的对照和MDD受试者的海马体，其已经表征了神经元和神经胶质的数量和大小的变化。此外，定制和商业微阵列将用于分析精神分裂症受试者的海马体，这将确定在抑郁症受试者中观察到的基因表达变化是否特异于MDD。改变的基因表达将通过独立的方法确认，包括RT-PCR和原位杂交。我们假设，这些研究产生的基因表达谱将导致更好地了解影响神经元萎缩，树突状分支，细胞死亡和细胞存活的机制。这些研究将为抑郁症患者海马区基因表达谱的研究提供重要信息，并将抗抑郁作用的分子机制与MDD的病因和治疗联系起来。

DESCRIPTION (provided by applicant): Brain imaging studies have reported that there is a reduction in the volume of the hippocampus of patients with major depressive disorder (MDD). In addition, preclinical studies demonstrate that stress decreases neurotrophic factor expression, reduces adult neurogenesis, and causes atrophy of neurons in the hippocampus. In contrast, studies in our laboratory and others have shown that chronic antidepressant treatment (ADT) increases the expression of neurotrophic factors and increases adult neurogenesis in the hippocampus. Taken together, these findings have contributed to a neurotrophic hypothesis of depression. While these preclinical results are interesting, information on their clinical relevance in the pathophysiology and treatment of MDD is lacking. The focus of the current application is to use microarray analysis to identify the molecular determinants that underlie the decrease in hippocampal volume. Toward this goal, we will characterize the gene expression profile of hippocampal subregions of depressed patients using a custom neurotrophic factor gene chip that we have developed. In addition, we will also use a human whole genome commercial microarray to identify other classes of genes altered in MDD. The hippocampus from matched control and MDD subjects that have already been characterized for changes in the number and size of neurons and glia will be used. In addition, the custom and commercial microarrays will be used for analysis of the hippocampus of schizophrenic subjects, which will determine if the gene expression changes observed in depressed subjects are specific to MDD. Altered gene expression will be confirmed by independent approaches, including RT-PCR and in situ hybridization. We hypothesize that the gene expression profiles generated by these studies will lead to a better understanding of the mechanisms that influence neuronal atrophy, dendritic arborization, cell death and cell survival. These studies will provide important information on the gene expression profile in hippocampus of depressed patients and a link between the molecular mechanism of antidepressant action and the etiology and treatment of MDD.