Project 1: Distinct Neural Phenotypes in Bipolar & Major Depression

项目 1：双相情感障碍的独特神经表型

• 批准号: 7483206
• 负责人: William E BUNNEY
• 金额: $ 57.3万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483206
• 关键词: Affect; Amygdaloid structure; Anterior; Applications Grants; Area; Autopsy; Biological; Bipolar Disorder; Brain; Brain region; Categories; Cerebellum; Classification; Data Set; Defect; Depth; Diagnostic; Disease; Etiology; Fibroblast Growth Factor; Fibroblasts; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Glutamates; Growth; Hippocampus (Brain); Human; Individual; Major Depressive Disorder; Medial; Methods; Mitochondria; Molecular Chaperones; Molecular Profiling; Mood Disorders; Moods; Nuclear; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Prefrontal Cortex; Prevention; Rattus; Schizophrenia; Signal Pathway; Structure; Study Section; System; Testing; Variant; base; brain tissue; cohort; gamma-Aminobutyric Acid; interest; mitochondrial dysfunction; mouse model; multicatalytic endopeptidase complex; neuropsychiatry; novel; promoter; protein function; relating to nervous system; response; serial analysis of gene expression; severe mental illness; suprachiasmatic nucleus

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.

该中心申请提出了两个相关的中心假设。 pdmary 假说认为，双相情感障碍 (BPD) 和重度抑郁症 (MDD) 这两种最严重的精神疾病在大脑中具有不同的神经表型或生物特征，这是通过一组不重叠的个体基因表达改变模式来识别的或功能相关的基因集合。第二个假设是，较小的一组基因将在两种疾病中表现出共同的表达改变，并且可能代表与共同脆弱性或大脑对这些疾病的共同反应有关的机制。该拨款提案将确认、表征和研究与 BPD 和 MDD 密切相关的选定基因和通路，与对照组和精神分裂症患者 (SZ)（包括成纤维细胞）相比 生长因子（FGF）系统相关基因和参与线粒体功能的基因。我们将通过检查涉及丘脑皮质配对结构的关键回路中基因的协调表达和调节来扩展对已识别基因的研究，测试它们在大鼠和小鼠情绪模型中的功能相关性，研究可能的机制。通过检查启动子变异来改变表达，并研究两个密切相关的系统：FGF 和线粒体。此外，为了更全面地定义与这两种疾病相关的不同神经表型，人类尸检 研究将扩展到其他边缘结构，并且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。鉴定出一组经过验证且可复制的基因和通路，可以预测 MDD（与 BPD 不同），这将为调查和确定这些疾病的病因以及确定治疗或预防的新靶点做出重大贡献。