NEURONAL VULNERABILITY AND INFORMATICS IN HUMAN DISEASE

人脑项目第一阶段的P20应用程序将 支持小组合作，开发计算机辅助定量 显微镜数据采集和分析软件，构建一个复杂的 基于脑图谱的层次关系型面向对象数据库 模板，并建立手段，使这些数据可以通过高 加速电子网络。 每个科学小组将使用 显微镜系统和计算机上的数据采集和分析系统 他们对相互关联的分子和细胞图谱的偏好 旨在揭示人类神经元易变性的研究 疾病 六名科学家将参与合作， 已经资助的研究项目的扩展：1）弗洛伊德布卢姆博士， 斯克里普斯研究所（TSRI），拉霍亚将是校长 研究者和拉霍亚TSRI的Warren Young博士将担任共同PI， 全面负责软件开发。 Bloom/Young项目 将开发3个关键的软件工具：a） 灵长类动物、猫科动物和啮齿类动物的神经系统（用作实验 基础，人免疫缺陷病毒综合征的动物模型）; B）a 主要脊椎动物的综合神经回路数据库 中枢神经系统; c）跨平台神经科学工作站 在局域网和广域网上运行的环境， 将5个研究项目和所需的项目联系起来， 数据采集、存储、分析和通信。 2)Dr. John 莫里森山纽约州纽约西奈医学院将开发第四个 Young的基本工具：计算机化显微镜数据采集 该系统集成了神经解剖学的实验范例， 从宏观到微观， 超微结构 莫里森项目将产生以下方面的定量数据： 灵长类动物和人类新皮层谷氨酸受体分布和其他 与神经变性脆弱性相关的分子（例如，神经丝 蛋白质）或抗性（例如，钙结合蛋白）。 3)哈维博士 Karten，UCSD医学院，拉霍亚将开发一个数据库， 脊椎动物的分子、细胞和生理特性 视网膜，并使用我们的组显微镜数据连接这个数据库 收集方法。 这个视网膜数据库将包括两个规范 成年和发育数据和病理变化，并比较 物种 4)拉霍亚加州大学圣地亚哥分校医学院的史蒂夫·富特博士将评估 多巴胺受体表达的定量长期变化（mRNA和 蛋白质）在灵长类动物的新皮层， 管理使用我们的组显微镜数据收集方法。 这些 多巴胺受体改变的结构参数将被整合 在面向对象的数据库中， 和原位微透析多巴胺释放数据。 5)爱德华·琼斯博士 加州大学欧文分校加州医学院，将采用计算机- 辅助显微镜方法，以量化特定的神经元群体， 人网状核和背侧丘脑的主要核团， 它们的免疫细胞化学定义的单胺和神经肽传入 成年精神分裂症患者大脑中的纤维系统， 帕金森病和阿尔茨海默病以及匹配的对照组， 妊娠中期的胎儿 这种规范性和疾病相关的数据 收集将定量测试的假设，活动- 基因表达和细胞形态的依赖性调节可 揭示了这些特殊的丘脑核团的功能性断开。 在 莫里森、富特、卡顿和琼斯项目的数据将被收集 从现有软件修改的通用格式， 进入并专门准备纳入大规模 地图集和数据库将由布卢姆/杨组件准备。 我们 将利用定量数据地图集和数据库， 细胞、电路和神经化学信息的规范， 然后用于检测和定义实验和病理变化， 并产生解释性假设。

This P20 application under Phase I of the Human Brain Project will support a group collaboration to develop computer-assisted quantitative microscopy data acquisition and analysis software, to construct a complex hierarchical, relational, object oriented database based on brain atlas templates, and establish means to make these data accessible through high speed electronic networks. Each of the scientific teams will use the data acquisition and analysis systems on microscope system and computers of their preference on inter-related molecular and cellular mapping studies designed to reveal neurons vulnerable to degeneration in human diseases. Six scientists will participate in the collaboration by extensions of already funded research projects: 1) Dr. Floyd Bloom, The Scripps Research Institute (TSRI), La Jolla will be Principal Investigator, and Dr. Warren Young, TSRI, La Jolla will be co-PI with overall responsibility for software development. The Bloom/Young Project will develop 3 critical software tools: a) digital atlases of the primate, feline, and rodent nervous systems, (using as an experimental base, animal models of human immunodeficiency virus syndrome); b) a comprehensive neuronal circuitry database for the major vertebrate central nervous systems; c) a cross-platform neuroscience workstation environment that operates on both local and wide area networks, interconnecting the 5 research projects, and the required programs for data acquisition, storage, analysis, and communication. 2) Dr. John Morrison, Mt. Sinai Medical School, New York, NY, will develop the fourth essential tool with Young: a computerized microscopy data acquisition system which integrates neuroanatomical paradigms of experimental observation at all levels of resolution from macroscopic to ultrastructure. The Morrison Project will generate quantitative data on primate and human neocortex glutamate receptor distribution and other molecules related to neurodegenerative vulnerability (e.g., neurofilament protein) or resistance (e.g., calcium binding proteins). 3) Dr. Harvey Karten, UCSD Medical School, La Jolla will develop a database of the molecular, cellular and physiological characteristics of vertebrate retinas, and link this database using our group microscope data collection methods. This retina database will include both normative adult and developmental data and pathological changes, and compare species. 4) Dr. Steve Foote, UCSD Medical School, La Jolla will evaluate quantitative long term changes in dopamine receptor expression (mRNA and protein) in the primate neocortex consequent to repeated psychostimulant administration using our group microscope data collection methods. These structural parameters of dopamine re-ceptor alteration will be integrated int he object oriented database with electrophysiological, behavioral, and in situ microdialysis dopamine release data. 5) Dr. Edward Jones, UC-Irvine California College of Medicine, will employ the computer- assisted microscopy methods to quantify specific neuronal populations in the major nuclei of the human reticular nucleus and dorsal thalamus and their immunocytochemically defined monoamine and neuropeptide afferent fiber systems in brains from adult patients with schizophrenia, Parkinson's disease and Alzheimer's disease and matched controls and in mid-trimester fetal material. This normative and disease-related data collection will quantitatively test the hypothesis that activity- dependent regulation of gene expression and cellular morphology can reveal functional disconnection of these particular thalamic nuclei. In the Morrison, Foote, Karten, and Jones Projects, data will be collected in common formats modified from existing software that are easily accessed and specifically prepared for incorporation into the large scale atlases and databases to be prepared by the Bloom/Young Component. We will utilize the quantitative data atlases and databases to establish norms of cellular, circuitry, and neurochemical information which will then serve to detect and define experimental and pathological variations, and to generate explanatory hypotheses.