Development of a Astroglia Maturation Gene Database

描述（申请人提供）：最近的研究已经认识到星形胶质细胞（星形胶质细胞）在中枢神经系统（CNS）功能中的重要作用，包括神经递质摄取，水运输，脑血流控制，离子缓冲，神经元突触形成/功能控制，感觉处理，昼夜节律和睡眠。星形胶质细胞也与几种神经退行性疾病有关，如癫痫、阿尔茨海默病（AD）、帕金森病（AD）和肌萎缩侧索硬化症（ALS），被认为是临床干预的潜在靶点。然而，星形胶质细胞如何发育成熟尚不清楚。同时，先前使用微阵列的基因表达谱研究已经允许表征和比较各种中枢神经系统细胞类型（包括星形胶质细胞）的基因表达模式。然而，微阵列在设计上受到探针偏差和无法检测未表征转录本的限制。此外，星形胶质细胞发育分子变化的详细数据库，特别是基因表达变化和选择性转录物剪接，目前还没有。基于我们对BAC ALDH1L1 TRAP小鼠和下一代测序（NGS）技术的初步研究，我们提出通过对体内不同发育阶段小鼠皮层中分离的星形胶质细胞翻译mrna进行测序，建立星形胶质细胞成熟过程中基因表达变化的数据库资源。此外，在出生后星形胶质细胞发育过程中，转录本的差异表达和基因替代转录本的程度将被确定。在二级分析中，还将分析发育各时间点的基因表达变化，以确定基因本体类别的富集程度、生化途径和富集程度最高的基因相互作用子网络。RNA-seq和二次分析的结果将与公共注释一起编译，并与其他可用的星形胶质细胞表达数据集成，并通过网络提供给神经科学界。它将可用于数据挖掘，这将促进星形胶质细胞的功能研究，并为神经系统疾病的临床干预提供目标。神经胶质生物学家（杨博士）和

DESCRIPTION (provided by applicant): Recent studies have recognized the significant roles of astroglia (astrocytes) in central nervous system (CNS) functions including neurotransmitter uptake, water transport, control of cerebral blood flow, buffering of ions, control of neuronal synapse formation/function, sensory processing, circadian rhythms and sleep. Astroglia have also been implicated in several neurodegenerative diseases such as epilepsy, Alzheimer's disease (AD), Parkinson's disease (AD) and amyotrophic lateral sclerosis (ALS) and are considered to be potential targets for clinical intervention. However, how astrocytes become developmentally mature is not well understood. In parallel, previous gene expression profiling studies using microarrays have allowed the characterization and comparison of gene expression patterns for various CNS cell types including astroglia. However, microarrays, by design are limited by the bias of the probes and inability to detect uncharacterized transcripts. I addition, a detailed database of the astroglial developmental molecular changes, in particular, gene expression change and alternative transcript splicing, is currently not available. Built on our preliminary studies on employing BAC ALDH1L1 TRAP mice and next generation sequencing (NGS) technologies, we propose to generate a database resource of gene expression changes during astroglia maturation, by sequencing astrocyte translating mRNAs isolated from mouse cortex at different developmental stages in vivo. Further, the differential expression of transcripts and the extent of alternative transcripts of genes during the postnatal astrocyte development will be determined. In the secondary analysis, the gene expression changes at each time point of the development will also be analyzed to determine the enrichment of gene ontology categories, biochemical pathways and top enriched gene interaction sub- networks. The results of RNA-seq and secondary analysis will be compiled together with public annotations and integrated with other available expression data on astrocytes and made available to the neuroscience community via the web. It will be available for data mining that will facilitate functional studies of astrocytes and provide targets for clinial intervention in neurological disorders. This collaboration between a glia biologist (Dr. Yang) and a computational biologist (Dr. Iyer) is at the Neuroscience department of Tufts University with a vibrant and collaborative glia research program led by Dr. Phil Haydon and Dr. Rob Jackson.