Mapping Cerebellar Development in Time and Space

描述(申请人提供)：小脑正在成为协调运动和认知行为的重要大脑区域。小脑发育异常与自闭症、精神分裂症和其他人类神经功能障碍有关。这项资助计划在30多个重组近交系小鼠(BXD)和15个单基因突变小鼠中获得广泛的新数据集，用于研究小脑发育的六个时期的基因表达和细胞表型。这些数据将通过WebQTL通过网络访问。我们还将开发和集成基于网络的信息学和可视化工具，供研究人员分析我们的数据集，提供他们自己的数据集用于分析，并测试关于小脑细胞和分子发育的假设。 提出了四个具体目标，这些目标将得到四个核心职能的支持。在目标1中，我们将获得RI和突变小鼠表达基因的全谱和几个可量化的发育过程的表型数据。这些数据将被整合到目前的数据库中，该数据库包含一系列关于成年小鼠大脑的特殊表型数据，WebQTL。在目标2中，我们将使用WebQTL、贝叶斯方法分析、图论方法识别表达数据中的集团，以及Medline参考文献的潜在语义索引来挖掘关于表达基因和细胞表型在时间和空间上的模式的数据。在目标3中，我们将使用分子(qRT-PCR)、解剖学(原位杂交和免疫细胞化学)和实验(SiRNA)方法来验证关于基因和表型关系的推断。最后，在目标4中，我们将开发一个网络可访问的、3D的、高端的小脑发育动画，用于启发式和实验目的。在这个项目中获得的数据和构建的工具将向研究界完全开放。该项目还被设计成与目前资助的几个人脑项目对接，这些项目着眼于成年小鼠大脑和小脑的解剖学和细胞生物学。收集的表型数据将有助于加深对小脑发育的分子和细胞基础的理解。这些信息可能有助于理解和治疗小脑起源的疾病，例如最常见的儿童脑癌--髓母细胞瘤，据信它源于小脑发育中的颗粒细胞。从长远来看，我们希望使用这个项目中开发的工具来预测对中枢神经系统的健康很重要的分子通路和细胞程序

DESCRIPTION (provided by applicant): The cerebellum is emerging as an important brain region for the coordination of motor and cognitive behaviors. Developmental abnormalities of the cerebellum have been linked to autism, schizophrenia, and other disorders of human neural function. This grant proposes to acquire extensive new data sets for gene expression and cellular phenotypes over six epochs of cerebellar development in over 30 recombinant inbred (RI) strains of mice (BXD) and 15 single gene mutant mice. This data will be web-accessible via WebQTL. We will also develop and integrate web-based informatic and visualization tools for researchers to analyze our data sets, provide datasets of their own for analysis, and test hypotheses about the cellular and molecular development of the cerebellum. Four specific aims are proposed that will be supported by four core functions. In Aim 1, we will obtain the phenotypic data on the full spectrum of expressed genes and several quantifiable developmental processes in RI and mutant mice. This data will be integrated into a current database that houses an exceptional array of phenotypic data on the adult mouse brain, WebQTL. In Aim 2, we will use WebQTL, Bayesian method analysis, graph theoretical approaches to the identification of cliques in expression data, and latent semantic indexing of Medline references to mine data on the patterns, both in time and space, of expressed genes and cellular phenotypes. In Aim 3, we will use molecular (qRT-PCR), anatomical (in situ hybridization and immunocytochemistry) and experimental (siRNA) approaches to validate inferences about gene and phenotype relationships. Finally, in Aim 4, we will develop a web-accessible, 3D, high-end animation of the developing cerebellum that will be used for heuristic and experimental purposes. The data that is obtained and the tools that are constructed in this project will be fully open to the research community. This project is also designed to interface with several of the currently funded Human Brain Projects that look at the anatomy and cell biology of the adult mouse brain and cerebellum. The phenotypic data that is gathered will contribute to the growing understanding of the molecular and cellular bases of cerebellar development. Such information may help understand and treat disorders of cerebellar origin, such as the most common form of childhood brain cancer, the medullablastoma, which is believed to emanate from the developing granule cells of the cerebellum. In the long term, we hope to use the tools developed in this project to make predictions about the molecular pathways and cellular programs that are important to the well-being of the central nervous system