CORE--MOLECULAR AND CELLULAR

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（Javitt，Kandel和Rayport的项目）。 对动物模型进行基因表达谱分析的基本原理是基于以下事实：发育和遗传操作均会诱导基因表达的长期变化，并且这些变化可能有助于动物模型的表型。根据皮质多巴胺能功能障碍将导致皮质下多巴胺功能失衡（皮质DA缺陷和纹状体DA过度活跃）的假设，我们预计gone表达的变化将发生在前额叶皮质和纹状体中（见中心的一般描述）。小鼠和猴子的表达谱不仅相互比较，而且还与精神分裂症患者的数据进行比较（与Karoly Mimics，匹兹堡大学合作）。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。 该中心还将对动物模型的组织进行组织病理学分析。神经病理学分析将用于多种目的，特别是1）提供定位基因表达和蛋白质水平变化所需的组织学体视学方案，并在细胞水平上对其进行定量，以及2）提供定性和定量的组织病理学？调查？的脑（细胞密度，细胞形态特征，区域体积），以评估模型是否复制精神分裂症中观察到的形态学和组织病理学异常。 一个？精神分裂症的特征可能是一个基因表达谱，是共同的几个操纵，诱导相同的星座的生理，行为，神经化学，和组织病理学表型。从这些研究中出现的候选基因将通过指向可能在精神分裂症中改变的特定神经元群体内的特定分子通路来告知该中心的人类组成部分（Abi-Dargham和Laruelle的项目，临床核心）。这些知识可能最终导致旨在纠正这些改变的新疗法的开发。

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.