Project 1: Distinct Neural Phenotypes in Bipolar & Major Depression

本中心的申请提出了两个相关的中心假设。该假说认为，两种最严重的精神疾病，双相情感障碍（BPD）和重性抑郁症（MDD）在大脑中具有不同的神经表型或生物学特征，如通过一组个体基因或功能相关基因集合的表达改变的非重叠模式所识别的。第二个假设是，一个较小的基因集将显示在两种疾病中的共同表达改变，并可能代表与共同的脆弱性或大脑对这些疾病的共同反应有关的机制。这项拨款提案将确认，表征和研究选定的基因和途径，这些基因和途径与对照组和精神分裂症（SZ）（包括成纤维细胞）相比，在BPD和MDD中有强烈的牵连 生长因子（FGF）系统相关基因和参与线粒体功能的基因。我们将扩大我们的研究所确定的基因，通过检查协调的表达和调控的基因的背景下，涉及丘脑-皮质配对结构的关键电路，测试其功能的相关性，在大鼠和小鼠模型的情绪，研究可能的机制改变表达通过检查启动子的变体和研究两个强烈牵连的系统，FGF和线粒体。此外，为了更全面地确定与这两种疾病相关的不同神经表型， 研究将扩展到更多的边缘系统结构，在当前队列中的预测将在一组新的BPD和MDD队列中进行测试，并与对照组进行对比。鉴定一组经验证和重复的基因和途径，可以预测MDD与BPD不同，这将为研究和鉴定这些疾病的病因以及鉴定治疗或预防的新靶点做出重大贡献。

This Center application proposes two related central hypotheses. The pdmary hypothesis is that two of the most serious mental illnesses, bipolar disorder (BPD) and major depressive disorder (MDD) have distinct neurophenotypes or biological signatures in the brain as identified by a set of non-overlapping patterns of altered expression of individual genes or functionally-related ensembles of genes. The secondary hypothesis is that a smaller set of genes will show common alterations in expression in the two diseases and may represent mechanisms relating to common vulnerability or a common response in the brain to these disorders. This grant proposal will confirm, characterize and study selected genes and pathways which are strongly implicated in BPD and MDD contrasted with controls and schizophrenics (SZ) including fibroblast growth factor (FGF) system-related genes and genes involved in mitochondrial function. We will extend our studies of the identified genes by examining the coordinated expression and regulation of the genes in the context of a critical circuit involving thalamo-cortical paired structures, test their functional relevance in rat and in mouse models of emotionality, investigate possible mechanisms of altered expression by examining promoter variants and study two strongly implicated systems, FGF and mitochondria. In addition, in order to more fully define the distinct neurophenotypes associated with these two disorders, the human postmortem studies will be expanded to additional limbic structures and the predictions adsing in the current cohorts will be tested in a new set of BPD and MDD cohorts contrasted with controls. The identification of a validated and replicated set of genes and pathways that could predict MDD as distinct from BPD would constitute a ;major contribution for investigating and for identifying the etiology of these disorders and identify novel targets for their treatment or prevention.