Gene Expression in Hippocampal Circuits of Bipolars and Schizophrenics

双相情感障碍和精神分裂症患者海马回路中的基因表达

• 批准号: 7916752
• 负责人: FRANCINE M. BENES
• 金额: $ 34.42万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-06 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916752
• 关键词: Accounting; Affect; Albumins; Amygdaloid structure; Antipsychotic Agents; Apoptosis; Apoptotic; Astrocytes; Autopsy; Bipolar Disorder; Calcium Binding; Calcium Channel; Cell Death; Cell Survival; Cells; Cholecystokinin; Data; Disease; Down-Regulation; Environmental Risk Factor; First Degree Relative; Fluorescence Resonance Energy Transfer; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Glutamates; Hippocampus (Brain); Human; In Situ Hybridization; Interneurons; L-Type Calcium Channels; Lead; Learning; MAPK14 gene; MAPK8 gene; Messenger RNA; Metabolic Pathway; Molecular; Molecular Profiling; Moods; Neuroglia; Neurons; Oligodendroglia; Oxidative Stress; Pathway interactions; Peptides; Phase; Picrotoxin; Psychotic Disorders; RNA; Rattus; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Rodent Model; Sampling; Schizophrenia; Signal Pathway; Signal Transduction; Stabilizing Agents; Staining method; Stains; Susceptibility Gene; Testing; Up-Regulation; Work; alveus; base; c-myc Genes; calbindin; calretinin; cohort; cresyl violet; follow-up; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; immunocytochemistry; laser capture microdissection; monoamine; neural circuit; novel; peptide G; phase 2 study; receptor

DESCRIPTION (provided by applicant): The studies described in this proposal are a logical follow-up to our earlier work showing subtle alterations of intrinsic neural circuitry in the hippocampus (HIPP) of schizophrenic (SZ) and bipolar disorder (BD) subjects. Some of these abnormalities have suggested that cellular and molecular changes in pathways associated with cell viability may lead to cell death in BDs and, to a lesser degree, SZs. We recently tested this hypothesis using gene expression profiling (GEP), together with a novel post hoc analysis of GenMapp biopathways/clusters. A pronounced upregulation of genes associated with calcium channels, monoamine and peptide G-coupled protein receptors (GPCRs) and multiple signaling pathways including apoptosis, TFG-p and Wnt has been observed in BDs. In SZs, these same pathways are affected, but in the opposite direction, suggesting that at least some of these changes may be related to susceptibility genes for each of the disorders. To learn more about cellular regulatory mechanisms in the HIPP of BDs and SZs, we are proposing to use two cohorts, one composed of a well-characterized set of normal controls, SZs and BDs called the McLean 66 and another consisting of first degree relatives of SZs (SZ-F) and matched controls. In Specific Aim I, a combination of GEP, laser capture microdissection (LCM) and quantitative RT-PCR will be used to determine whether these changes are present in particular subregions, sublaminae and cellular subtypes in sectors CA3/2 versus CA1 in HIPP of BDs and SZs. In later studies, we will perform GEP in the SZ-F cohort to determine whether there are similarities in the expression profiles in SZs. In addition, data from our 'partial' rodent model of SZ in which picrotoxin is acutely and chronically infused in the amygdala will also be used to evaluate whether genes showing overlapping changes in BDs, SZs and PICRO-treated rats may be related to amygdalar activation of the HIPP. In Specific Aim II, we will validate and extend the GEP results by using double in situ hybridization (DISH) to co-localize mRNA from several target genes associated with apoptosis and other GenMapp pathways/clusters with GAD65 mRNA to determine whether key changes are preferentially occurring in GABAergic or non-GABAergic neurons. Overall, the proposed studies are seeking to replicate, validate and extend our GEP studies in critical ways that will provide a more detailed understanding of where pivotal changes in gene expression may be occurring within discrete aspects of HIPP circuitry and whether such changes may be related to genetic or environmental factors associated with the psychotic disorders.

描述（由申请人提供）：本提案中描述的研究是我们较早的工作的逻辑随访，表明精神分裂症（SZ）和双相情感障碍（BD）受试者海马（HIPP）中内在神经回路的细微变化。其中一些异常表明，与细胞活力相关的途径的细胞和分子变化可能会导致BDS的细胞死亡，并且在较小程度上会导致SZS。我们最近使用基因表达分析（GEP）测试了这一假设，以及对GenMAPP Biopathways/clusters的新事后分析。在BDS中，已经观察到与钙通道，单胺和肽G偶联蛋白受体（GPCR）以及包括凋亡，TFG-P和WNT在内的多个信号通路相关的基因的明显上调。在SZ中，这些相同的途径受到影响，但在相反的方向上，表明其中一些变化可能与每个疾病的易感基因有关。为了更多地了解BDS和SZS河流中的细胞调节机制，我们建议使用两个同类群体，一种由一组良好的正常对照组组成，SZS和BDS，称为McLean 66，另一个由SZS（SZ-F）（SZ-F）（SZ-F）（SZ-F）（SZ-F）和匹配的控件组成。在特定的目标I中，将使用GEP，激光捕获显微解剖（LCM）和定量RT-PCR的组合来确定BDS和SZS中HIPP和SZS中CA1中的CA3/2中的Sublaminae和sublaminae和细胞子类型是否存在这些变化。在以后的研究中，我们将在SZ-F队列中执行GEP，以确定SZS中表达曲线的相似性。此外，我们的“部分”啮齿动物模型的数据在杏仁核中急性和慢性注入，还将用于评估显示出显示BDS，SZS和PICRO治疗大鼠重叠变化的基因是否可能与Hipp的杏仁核激活有关。在特定目标II中，我们将使用双重原位杂交（DIS）来验证和扩展GEP结果，以将与凋亡和其他具有GAD65 mRNA的其他靶基因和其他GenMAPP途径/簇相关的靶基因共定位mRNA，以确定关键变化是否优先发生在GABA抗剂或非gabaergaergaergagaer ogragric神经元中。总体而言，拟议的研究正在寻求以关键方式复制，验证和扩展我们的GEP研究，这些研究将对基因表达的关键变化在HIPP电路的离散方面可能发生更详细的理解，以及这种变化是否可能与与精神疾病相关的遗传或环境因素有关。