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

项目摘要（参见说明）： 产前损伤是发病和死亡的一个重要原因，通常会造成长期的认知后遗症。在高度敏感的发育时期所造成的不同形式的伤害越来越多地产生类似的表型，包括行为和认知缺陷以及精神发育迟滞。重要的是，最常见形式的发育性脑损伤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 重点研究细胞外环境在正常中枢神经系统 (CNS) 发育期间和创伤性胚胎脑损伤后促进胶质细胞谱系细胞的规范和迁移中的作用。最近的几项发现为未来的研究提供了信息：证明聚集蛋白聚糖在胶质生成中的作用；建立忠实再现天然体内细胞结构和细胞的后脑器官培养系统 环境；以及急性胚胎损伤模型的开发，使得能够研究胚胎损伤后基质的保护或抑制作用。提出两个目标： 目标1，分析胶质细胞迁移和分化以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以及蛋白多糖在此过程中的功能。这些研究将深入了解星形胶质细胞生成的控制机制以及神经胶质细胞前体环境成分对细胞命运的影响，并阐明神经胶质细胞前体分化如何受到大脑发育过程中创伤引起的细胞环境变化的影响。了解这些关系背后的机制对于能够重塑细胞外环境的组成至关重要，从而影响发育过程中的细胞命运，并设计出新的疗法来促进中枢神经系统损伤后的再生。

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.