Molecular Alterations of Cortical Layer 3 Pyramidal Cells in Schizophrenia

精神分裂症皮质第 3 层锥体细胞的分子改变

• 批准号: 9355826
• 负责人: ETIENNE L SIBILLE
• 金额: --
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355826
• 关键词: Address; Affect; Alcohol or Other Drugs use; Alcohols; Antipsychotic Agents; Area; Attention; Autopsy; Biological; Brain region; Cells; Characteristics; Cognition; Data Set; Disease; Drug Targeting; Electrophysiology (science); Energy Metabolism; Equilibrium; Future; Gene Expression; Gene Expression Alteration; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Group Identifications; Human; Image; Indium; Instruction; Lasers; Measures; Mediating; Messenger RNA; MicroRNAs; Microdissection; Molecular; Molecular Abnormality; Molecular Profiling; Molecular Target; Monkeys; Neocortex; Network-based; Neurons; Parietal Lobe; Parvalbumins; Pathology; Pathway interactions; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Process; Property; Pyramidal Cells; Regulator Genes; Regulatory Element; Regulatory Pathway; Sampling; Schizoaffective Disorders; Schizophrenia; Severities; Short-Term Memory; Specificity; Synapses; Testing; Therapeutic; Tissues; Transcript; Vertebral column; Visual; Visual Cortex; area striata; base; cell type; cellular targeting; cohort; differential expression; disorder control; gamma-Aminobutyric Acid; gene product; human subject; insight; interest; mRNA Expression; molecular pathology; nano-string; nonhuman primate; novel; protein biomarkers; regional difference; response; suicidal morbidity; targeted treatment; therapeutic target

Project 1 (P1) provides molecular tests at the cell type-specific level for the following aspects of the Central Hypothesis: 1) a core cortical pathology in schizophrenia affects layer 3 pyramidal cells, and 2) the impact of this pathology on gene expression is moderated by factors that differ across cortical regions. Layer 3 pyramidal cells will be collected using laser microdissection in postmortem samples from subjects with schizophrenia or schizoaffective disorder and healthy comparison subjects (Aim 1). Within-region analyses will inform on the cell autonomous pathology of layer 3 pyramidal cells in schizophrenia. Across-region analyses will characterize molecular regional specificities in control subjects and how they impact the pathology of layer 3 pyramidal cells in schizophrenia. A secondary goal is to gain insight into potential molecular targets to restore functional balance along the visual working memory and attention network. Accordingly, since layer 3 pyramidal cell alterations are predicted to induce transcriptional responses in the parvalbumin (PV)-containing GABA neurons that they innervate, similar analyses will be performed in PV neurons (Aim 2). To provide a comprehensive molecular perspective on coordinated local circuit alterations, expression of genes (mRNA) and gene regulatory micro-RNAs (miRNA) will be investigated in parallel (Aims 1-2) and biological modules implicated in healthy control and pathological conditions will be identified by changes in coordinated expression across cell types, regions and cohorts (Aim 3). Results from PI will inform all other Center projects on the molecular and cellular bases in regards to the Central Hypothesis that regional differences moderate the serverity of layer 3 PC alterations in schizophrenia. PI will also provide molecular leads for protein marker studies in P2, and for layer 3 PC regional differences in electrophysiological properties in P3. Together Projects 1-3 will provide the molecular, cellular and circuitry bases for the functional connectivity studies in monkey (P4), and in imaging studies of healthy controls and subjects with schizophrenia (P5).

项目1（P1）提供细胞类型特异性水平的分子测试，用于以下方面的中央 假设：1）精神分裂症的核心皮质病变影响第3层锥体细胞，2） 这种基因表达的病理学受到不同皮质区域的因素的调节。层3 将使用激光显微切割从患有以下疾病的受试者的尸检样本中收集锥体细胞： 精神分裂症或情感性精神障碍和健康对照受试者（目标1）。区域内分析 将告知精神分裂症中第3层锥体细胞的细胞自主病理学。跨区域 分析将表征对照受试者中的分子区域特异性，以及它们如何影响 精神分裂症第三层锥体细胞病理学研究第二个目标是洞察潜在的 分子靶点，以恢复沿着视觉工作记忆和注意力网络的功能平衡。 因此，由于预测第3层锥体细胞的改变会诱导细胞中的转录应答， 在含有小清蛋白（PV）的GABA神经元，它们支配，类似的分析将在PV 神经元（Aim 2）。为了提供关于协调的局部电路改变的全面分子观点， 将平行研究基因（mRNA）和基因调节微RNA（miRNA）的表达（目的 1-2)和涉及健康对照和病理条件的生物模块将通过 跨细胞类型、区域和群组的协调表达的变化（目标3）。PI的结果将 通知中心所有其他关于中心假说的分子和细胞基础的项目， 地区差异缓解了精神分裂症第3层PC改变的严重程度。PI还将提供 P2中蛋白质标记研究的分子先导物，以及P2中第3层PC区域差异的分子先导物。 P3的电生理特性项目1-3将共同提供分子、细胞和电路 猴（P4）功能连接研究和健康对照成像研究的基础， 精神分裂症患者（P5）。