Underlying Molecular Mechanisms of Gliogenesis and Gliomagenesis in the Central Nervous System

 描述(申请人提供)：胶质细胞，由星形胶质细胞和少突胶质细胞组成，是中枢神经系统中最增殖和最丰富的细胞类型。星形胶质细胞和少突胶质细胞的异常发育与许多神经系统疾病和障碍有关，如肌外侧硬化症(ALS)、多发性硬化症(MS)、自闭症、癫痫、精神分裂症和脑胶质母细胞瘤，后者是最致命的脑癌。碱性螺旋环状螺旋转录因子Ascl1和Opol2对星形胶质细胞和少突胶质细胞的分化和发育起着至关重要的作用，在胶质母细胞瘤中高表达。该项目旨在：1)确定Ascl1和Otl2在调节脊髓灰质和白质中星形胶质细胞和少突胶质细胞的生成中的角色和功能；2)确定Ascl1和Otl2在小鼠脑胶质母细胞瘤模型中的体内需求；以及3)利用下一代测序技术在全基因组水平上确定Ascl1和Otl2在胶质前体细胞中的DNA结合谱和直接转录靶基因，并将其与胶质母细胞瘤小鼠模型中的肿瘤细胞进行比较。这项研究的结果将导致对中枢神经系统中胶质细胞异质性和胶质母细胞瘤发展的遗传调控网络的新见解。

 DESCRIPTION (provided by applicant): Glia, which constitutes astrocytes and oligodendrocytes, are the most proliferative and abundant cell types in the central nervous system. Abnormal development of astrocytes and oligodendrocytes is associated with a number of neurological diseases and disorders such as amyolateral sclerosis (ALS), multiple sclerosis (MS), autism, epilepsy, schizophrenia, and glioblastoma, the deadliest of brain cancers. The basic-helix-loop-helix (bHLH) transcription factors Ascl1 and Olig2 are crucial for the specification and development of both astrocytes and oligodendrocytes, and are highly expressed in glioblastoma. The proposed project aims to: 1) determine the role and function of Ascl1 and Olig2 in regulating the generation of astrocytes and oligodendrocytes in the gray matter and white matter in the spinal cord; 2) determine the in vivo requirement of Ascl1 and Olig2 in brain tumors of a mouse model of glioblastoma; and 3) utilize Next-Generation sequencing techniques to identify on a genome-wide scale the DNA-binding profiles and direct transcriptional target genes of Ascl1 and Olig2 in glial progenitors in comparison to tumor cells of the glioblastoma mouse model. The culmination of this study will lead to new insights on the genetic regulatory networks of glial heterogeneity and glioblastoma development in the central nervous system.