Proj 1: Influeence of proteoglycans on Gliogeness and Embryonic Brain Injury

项目总结（见说明）： 产前损伤是一个重要的发病率和死亡率的原因，往往与长期的认知后遗症。越来越多的不同形式的伤害，在高度敏感的发展时期造成类似的表型，涉及行为和认知缺陷和智力迟钝。重要的是，发育性脑损伤最常见形式的易感期与少突胶质细胞和星形胶质细胞的分化和成熟相一致。项目1的重点是在正常中枢神经系统（CNS）发育过程中和创伤性胚胎脑损伤后，细胞外环境在促进胶质细胞谱系的特异性和迁移中的作用。最近的几项发现为未来的研究提供了信息：证实了聚集蛋白聚糖在胶质细胞生成中的作用;建立了一个忠实地再现了体内细胞结构和细胞生长的后脑器官型培养系统。 环境;以及开发急性胚胎损伤模型，使得能够研究胚胎损伤后基质的保护或抑制作用。提出了两个目标：目的1、分析胶质细胞迁移和分化过程及细胞外环境的重要性;目的2、阐明胶质前体细胞对胚胎脑损伤的反应及蛋白多糖在此过程中的作用。这些研究将为控制星形胶质细胞发生的机制和胶质细胞前体细胞环境组分对细胞命运的影响提供见解，并阐明胶质细胞前体分化如何受到脑发育过程中创伤诱导的细胞环境变化的影响。理解这些关系的基础机制对于能够重塑细胞外环境的组成，从而影响发育过程中的细胞命运，以及设计新的治疗方法以促进CNS损伤后的再生至关重要。

PROJECT SUMMARY (See instructions): Prerinatal injury is a significant cause of morbidity and mortality, often with long term cognative sequelae. Increasingly, different forms of injury inflicted during highly susceptible periods of development produce similar phenotypes involving behavioral and cognitive deficits and mental retardation. Importantly, the susceptibility period for the most common forms of developmental brain injuries coincides with oligodendrocyte and astrocyte differentiation and maturation. Project 1 focuses on the role of the extracellular milieu in promoting specification and migration of cells of the glial lineage during normal central nervous system (CNS) development and after traumatic embryonic brain injury. Future studies are informed by several recent findings: the demonstration of a role for aggrecan in gliogenesis; establishment of a hindbrain organotypic culture system which faithfully recapitulates the native in vivo cytoarchitecture and cell environment; and development of an acute embryonic injury model enabling the study of the protective or inhibitory role of the matrix following embryonic injury. Two aims are proposed: Aim 1, To analyze glial cell migration and differentiation and the importance of the extracellular milieu; Aim 2, To elucidate the response of glial precursors to embryonic brain injury and the function of proteoglycans in this process. These studies will provide insights into mechanisms controlling astrogliogenesis and the influence of components of the glial cell precursors' environment on cell-fates, as well as elucidate how glial precursor differentiation is affected by cell-environment changes induced by trauma during brain development. Understanding the mechanisms which underlie these relationships is critical to being able to remodel the composition of the extracellular milieu, thereby influencing cell-fate during development, and devising novel therapies to foster regeneration after CNS injury.