CORE--MOLECULAR AND CELLULAR

核心——分子和细胞

• 批准号: 7457817
• 负责人: Rene Hen
• 金额: $ 14.84万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7457817
• 关键词: Animal Model; Behavioral; Candidate Disease Gene; Cell Density; Clinical; Collaborations; Corpus striatum structure; Data; Development; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Glutamates; Goals; Human; Hyperactive behavior; Knowledge; Lead; Localized; Modeling; Molecular; Molecular Profiling; Monkeys; Mus; Neurons; Pathway interactions; Patients; Phenotype; Physiological; Population; Prefrontal Cortex; Proteins; Protocols documentation; Purpose; Resources; Schizophrenia; Surveys; Technology; Tissues; Universities; base; brain cell; developmental genetics; genetic manipulation; neurochemistry

The goal of the Molecular and Cellular Core is to provide the resources and technologies to study gene expression and to assess putative neuropathological changes in the animal models being developed in the Center (Projects by Javitt, Kandel, and Rayport). The rationale for performing gene expression profiling on animal models is based on the fact that the developmental and genetic manipulations will all induce long lasting changes in gene expression and that these changes are likely to contribute to the phenotype of the animal models. In keeping with the hypothesis that cortical glutamatergic dysfunction will result in an imbalance in subcortical dopamme function (cortical DA deficit and striatal DA hyperactivity), we expect that changes in gone expression will take place both in the prefrontal cortex and in the striatum (See general description of the Center). The mouse and monkey expression profiles will be compared not only with one another but also with data from schizophrenic patients (collaboration with Karoly Mimics, University of Pittsburgh). These multiple comparisons should enable us to establish correlations between specific gene expression profiles and the physiological and behavioral phenotypes of the animal models. This Core will also perform histopathological analyses of the tissue from the animal models. The neuropathological analysis will serve multiple purposes, notably 1) to provide histological stereological protocols necessary to localize changes in gene expression and protein levels and quantify them at the cellular level and 2) to provide qualitative and quantitative histopathological ?survey? of the brain (cell density, cell morphological profiles, regional volume) to assess if the models replicate the morphometric and histopathological abnormalities observed in schizophrenia. A ?schizophrenia signature? may be a gene expression profile that is common to several manipulations that induce the same constellation of physiological, behavioral, neurochemical, and histopathological phenotypes. The candidate genes, which will emerge from these studies, will inform the human components of this Center (Projects by Abi-Dargham and Laruelle), clinical Core) by pointing toward specific molecular pathways within specific neuronal populations that may be altered in schizophrenia. Such knowledge may ultimately lead to the development of new therapies aimed at correcting these alterations.

分子和细胞核心的目标是提供资源和技术来研究基因表达并评估该中心正在开发的动物模型中假定的神经病理学变化（项目由 Javitt、Kandel 和 Rayport 负责）。 在动物模型上进行基因表达谱分析的基本原理是基于以下事实：发育和遗传操作都会诱导基因表达的长期持续变化，并且这些变化可能会导致动物模型的表型。与皮质谷氨酸功能障碍将导致皮质下多巴胺功能失衡（皮质 DA 缺乏和纹状体 DA 过度活跃）的假设相一致，我们预计 gone 表达的变化将同时发生在前额皮质和纹状体中（见概述）中心的描述）。小鼠和猴子的表达谱不仅会相互比较，还会与精神分裂症患者的数据进行比较（与匹兹堡大学 Karoly Mimics 合作）。这些多重比较应该使我们能够 建立特定基因表达谱与动物模型的生理和行为表型之间的相关性。 该核心还将对动物模型的组织进行组织病理学分析。神经病理学分析将服务于多种目的，特别是1）提供定位基因表达和蛋白质水平的变化并在细胞水平上量化它们所必需的组织学体视学方案，2）提供定性和定量的组织病理学“调查”。大脑的结构（细胞密度、细胞形态特征、区域体积），以评估模型是否复制了精神分裂症中观察到的形态和组织病理学异常。 “精神分裂症签名”？可能是诱导相同的生理、行为、神经化学和组织病理学表型的几种操作所共有的基因表达谱。这些研究中出现的候选基因将通过指向特定神经元群体内可能在精神分裂症中改变的特定分子途径，为该中心的人类组成部分（Abi-Dargham 和 Laruelle 的项目）、临床核心）提供信息。这些知识最终可能会导致旨在纠正这些改变的新疗法的开发。