Non-Radial Cell Migration in CNS Development

中枢神经系统发育中的非径向细胞迁移

• 批准号: 6839414
• 负责人: Jeffrey A Golden
• 金额: $ 28.26万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839414
• 关键词: Non; Radial; Cell; Migration; CNS

EXCEED THE SPACE PROVIDED. Epilepsy, mental retardation and structural anomalies of the brain often have a genetic etiology. Although they affect 3-5% of all children, the underlying pathogeneses for these disorders is poorly understood in most cases. Cell migration is a central component of normal central nervous system (CNS) development and disruptions in this process have been implicated in the development of multiple disorders such as Fukuyama Muscular dystrophy, Miller-Dieker Syndrome, Walker-Warburg Syndrome, and the Muscle-Eye-Brain syndrome to name just a few. Two primary patterns of cell migration are recognized during CNS development, radial and non-radial. While the cellular and molecular bases of radial cell migration, long considered the predominant mode of cell migration, have begun to be defined, the mechanisms of guidance for non-radial cell migration remain largely unexplored. Using lineage analysis, we have defined the developmental time and location where non-radial cell migration begins in the chick forebrain. Based on these data we have developed a model to explain the cellular and molecular mechanisms of non-radial cell migration. Our model is based on the hypotheses that cell surface molecules, secreted molecules, and extracellular matrix molecules guide non-radially migrating cells. This proposal will begin to address our hypothesis by 1) directly testing several components of our model, and 2) generate a mammalian model to further study one of the molecules we have identified as a component of non-radial cell migration in the chick. These data will certainly enhance our understanding of normal CNS development. Furthermore, we anticipate the data from these studies will provide insight into the pathogenesis of a variety of inherited and non-inherited conditions that afflict children such as epilepsy, mental retardation and structural malformations of the brain. This may ultimately lead to improvements in the diagnosis, management, and prevention of neurological diseases where abnormal cell migration has a pathogenetic role. PERFORMANCESITE( ========================================Section End===========================================

超出提供的空间。癫痫、智力低下和大脑结构异常通常有遗传病因。尽管这些疾病影响了3-5%的儿童，但在大多数情况下，这些疾病的潜在发病机制尚不清楚。细胞迁移是正常中枢神经系统(CNS)发育的中心组成部分，这一过程中的干扰已被认为与多种疾病的发展有关，如福山肌营养不良症、Miller-Dieker综合征、Walker-Warburg综合征和肌肉-眼-脑综合征等等。在中枢神经系统发育过程中，细胞迁移的两种主要模式被认为是径向和非径向的。虽然长期以来被认为是主要细胞迁移方式的径向细胞迁移的细胞和分子基础已经开始被确定，但指导非径向细胞迁移的机制在很大程度上仍未被探索。利用谱系分析，我们已经确定了雏鸡前脑中非放射状细胞迁移开始的发育时间和位置。基于这些数据，我们开发了一个模型来解释非径向细胞迁移的细胞和分子机制。我们的模型是基于细胞表面分子、分泌分子和细胞外基质分子引导细胞非放射状迁移的假设。这一建议将通过以下方式开始解决我们的假设：1)直接测试我们模型的几个组件，以及2)生成一个哺乳动物模型，以进一步研究我们已确定为雏鸡非放射状细胞迁移组件的一个分子。这些数据肯定会加深我们对中枢神经系统正常发育的理解。此外，我们预计来自这些研究的数据将为各种遗传性和非遗传性疾病的发病机制提供洞察力，这些疾病困扰着儿童，如癫痫、智力低下和大脑结构畸形。这可能最终导致神经疾病的诊断、管理和预防方面的改进，在这些疾病中，异常细胞迁移具有致病作用。PERFORMANCESITE(========================================Section End===========================================