Genomic Studies in Bipolar and Major Depression

描述（由申请人提供）：双相情感障碍和抑郁障碍的神经表型：中心申请提出测试两个相关假设。主要的假设是，两种最严重的情绪障碍，双相情感障碍（BPD）和重度抑郁症（MDD）在大脑中具有不同的神经表型或生物学特征，通过个体基因表达模式或功能相关基因集合的一组非重叠改变来识别。第二种假设是，在这些疾病中，一组较小的基因会显示出共同的变化，可能代表着与情绪障碍的共同脆弱性或对这些疾病对大脑的共同影响相关的机制。项目1对这些假设的调查有三个目的。目的一：确认、表征和研究与对照和精神分裂症患者相比，与BPD和MDD密切相关的选定基因和途径。实现Aim 1目标的方法包括qRT -PCR、原位杂交研究、Western blot蛋白功能研究和SAGE（基因表达序列分析）。我们选择了两个研究结果进行深入的表征和研究（FGF系统在MDD中显著失调，线粒体功能障碍在MDD和BPD中都有密切关系）。目的1将微阵列研究扩展到BPD和MDD患者与对照组相比的额外边缘和非边缘结构。科学界一致认为，边缘系统是BPD和MDD病理生理的关键回路。这将是第一个评估控制组和情绪障碍患者3种边缘结构基因表达的研究。目的3将测试盲目预测和区分BPD与MDD和SZ的能力。基于初始队列定义的神经表型，在15名BPD， 15名MDD和15名对照的新队列中预测和区分BPD， MDD和SZ。来自以下数据集的信息将用于预测分析：BPD和MDD的独特非重叠基因；相同基因在BPD和MDD中呈相反方向显著差异；BPD和MDD之间共有的基因；BPD和MDD的GO和KEGG通路及功能分析。鉴别出能够预测重度抑郁症和BPD不同的、经过验证和复制的基因和途径，将对研究这些疾病的病因和治疗做出重大贡献。确定新的治疗或预防目标。这些调查与其他中心项目有许多概念和技术联系，并依赖于所有拟议核心提供的支持。

DESCRIPTION (provided by applicant): Neural Phenotypes in Bipolar & Depressive Disorders: The Center application proposes to test two, related hypotheses. The primary hypothesis is that two of the most serious mood disorders, bipolar disorder (BPD) land major depressive disorder (MDD) have distinct neural phenotypes or biological signatures in the brain as identified by a set of non-overlapping alterations in the pattern of expression of individual genes or functionally related ensembles of genes. The secondary hypothesis is that a smaller set of genes will show alterations in common in these diseases and may represent mechanisms related to common vulnerability to mood disorders or a common impact to those disorders on the brain. Project 1 contributes to the investigation of these hypotheses with three Aims. Aim I: Confirm, characterize and investigate selected genes and pathways which are strongly implicated in BPD and MDD contrasted with controls and schizophrenics. Methods to be employed to achieve the goals of Aim 1 include qRT -PCR, in situ hybridization studies, Western blot protein function studies and SAGE (serial analyses of gene expression). Two findings have been selected for in-depth characterization and study (The FGF system which was significantly dysregulated in MDD and mitochondrial dysfunction which is strongly implicated in both MDD and BPD). Aim l will extend the microarray studies to additional limbic and non-limbic structures in BPD and MDD contrasted with controls. There is scientific consensus that the limbic system is a key circuit in the pathophysiology of BPD and MDD. This will represent the first study evaluating gene expression in 3 limbic structures in controls and mood disorder patients. Aim 3 will test the ability to blindly predict and discriminate BPD from MDD and SZ. Based on the neural phenotypes defined by the initial cohorts, predict and discriminate BPD, MDD from SZ in a new cohort of 15 BPD, 15 MDD and 15 controls. Information derived from the following sets of data will be utilized in the predictive analyses: Unique non- overlapping genes for BPD and MDD; the same genes significantly different in opposite directions in BPD and MDD; genes shared in common between BPD and MDD; GO and KEGG pathway and function analyses of BPD and MDD. The identification of validated and replicated genes and pathways that can predict MDD as distinct from BPD will constitute a major contribution to investigating the etiology of these disorders and toward! identifying novel targets for their treatment or prevention. These investigations have many conceptual and technical links with other Center projects and depend on the support provided by all of the proposed Cores.