NEURONAL VULNERABILITY AND INFORMATICS IN HUMAN DISEASE

人脑计划第一阶段下的P20应用程序将 支持小组协作开发计算机辅助定量 显微镜数据采集与分析软件，构建复合体 基于脑图谱的层次化、关系型、面向对象数据库 模板，并建立使这些数据可通过高级访问的方法 高速电子网络。每个科学团队都将使用 显微镜系统和计算机上的数据采集与分析系统 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。六名科学家将通过以下方式参与合作 延长已经资助的研究项目：1)弗洛伊德·布鲁姆博士， 斯克里普斯研究所(TSRI)，La Jolla将担任院长 调查员和TSRI的Warren Young博士，La Jolla将与PI共同 全面负责软件开发。Bloom/Young项目 将开发3个关键软件工具：a)数字地图集 灵长类、猫科动物和啮齿动物神经系统(用作实验动物 基础，人类免疫缺陷病毒综合症的动物模型)； 主要脊椎动物的全面神经元电路数据库 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， 相互关联的5个研究项目和所需的计划 数据采集、存储、分析和通信。2)约翰博士 莫里森，Mt.纽约州纽约的西奈医学院将开发第四种 杨的必备工具：计算机化显微镜数据采集 整合实验神经解剖学范式的系统 所有分辨率级别的观测，从宏观到 超微结构。莫里森项目将产生关于 灵长类和人类新皮质谷氨酸受体的分布及其他 与神经退行性变易损性相关的分子(如神经丝 蛋白质)或抗性(例如，钙结合蛋白)。3)哈维博士 加州大学洛杉矶分校医学院的Karten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，并使用我们的群体显微镜数据链接这个数据库 收集方法。这个视网膜数据库将包括标准的 成人和发育的数据和病理变化，并比较 物种。4)加州大学洛杉矶分校医学院的Steve Foote博士将对 多巴胺受体表达的长期定量变化(mRNA和 蛋白质)在灵长类动物的新皮质中的作用 行政管理采用我们的组镜数据收集方法。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包含电生理、行为、 和原位微渗析的多巴胺释放数据。5)爱德华·琼斯博士， 加州大学欧文分校医学院将使用计算机- 用辅助显微镜方法对脑内特定神经元群体进行量化 人网状核和丘脑背侧的主要核团和 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， 帕金森氏病和阿尔茨海默病和匹配的对照组 妊娠中期的胎儿物质。这些规范性和与疾病相关的数据 收集将定量地检验活动- 对基因表达和细胞形态的依赖调节可以 揭示了这些特定丘脑核团的功能性分离。在……里面 将收集莫里森、福特、卡腾和琼斯项目的数据 以从现有软件修改的通用格式，这些格式很容易 进入并特别准备纳入大规模 地图集和数据库将由Bloom/Young部门编制。我们 将利用量化数据地图集和数据库建立 细胞、电路和神经化学信息的规范 然后用来检测和定义实验和病理变异， 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.