Genomic Studies in Bipolar and Major Depression

双相情感障碍和重度抑郁症的基因组研究

• 批准号: 7123364
• 负责人: William E BUNNEY
• 金额: $ 182.96万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123364
• 关键词: bipolar depression; clinical research; gene expression; major depression; neurogenetics; neuropathology; phenotype; psychobiology

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.

描述（由申请人提供）：双相情感障碍和抑郁症的神经表型：该中心申请建议测试两个相关的假设。主要假设是，双相情感障碍（BPD）和重度抑郁症（MDD）这两种最严重的情绪障碍在大脑中具有不同的神经表型或生物特征，通过一组不重叠的表达模式改变来识别单个基因或功能相关的基因集合。第二个假设是，一小部分基因将显示这些疾病中常见的改变，并且可能代表与常见的情绪障碍易感性或这些疾病对大脑的常见影响相关的机制。项目 1 通过三个目标对这些假设进行调查。目标 I：与对照组和精神分裂症患者相比，确认、表征和研究与 BPD 和 MDD 密切相关的选定基因和通路。实现目标 1 的目标所采用的方法包括 qRT -PCR、原位杂交研究、Western blot 蛋白功能研究和 SAGE（基因表达的系列分析）。选择了两项研究结果进行深入表征和研究（MDD 中显着失调的 FGF 系统以及与 MDD 和 BPD 密切相关的线粒体功能障碍）。目标 l 将微阵列研究扩展到与对照组相比的 BPD 和 MDD 的其他边缘和非边缘结构。科学界一致认为边缘系统是 BPD 和 MDD 病理生理学的关键回路。这将是第一项评估对照组和情绪障碍患者 3 个边缘结构基因表达的研究。目标 3 将测试盲目预测和区分 BPD 与 MDD 和 SZ 的能力。根据初始队列定义的神经表型，在由 15 个 BPD、15 个 MDD 和 15 个对照组成的新队列中预测和区分来自 SZ 的 BPD、MDD。 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 中的相反方向显着差异； BPD 和 MDD 共有基因； BPD和MDD的GO和KEGG通路及功能分析。鉴定出经过验证和复制的基因和通路，可以预测 MDD（与 BPD 不同），这将为研究这些疾病的病因学和实现这一目标做出重大贡献！确定治疗或预防的新目标。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。