Glycolipids of Neural Stem Cells

神经节苷脂是一种糖基化鞘脂，在脑发育中具有重要但神秘的功能 和神经干细胞（NSC）维持。我们对神经节苷脂功能的认识的一个关键障碍是， 缺乏针对NSC分化中关键调控机制的系统方法 由神经节苷脂指导。我们小组率先研究了神经节苷脂对生长的重要性 因子受体信号传导和神经干细胞的表观遗传调控。该项目的总体目标是进一步 阐明神经节苷脂在神经干细胞的功能作用的基础上当代的概念和技术。的 鞘糖脂（GSL）在细胞表面微区的主要定位和剧烈剂量， 神经分化过程中的组成变化强烈表明GSL不仅重要， 生物标志物，而且还参与调节NSC功能。NSC中的许多阶段特异性GSL抗原是 目前已知，但对其调节NSC细胞的生物学功能机制了解较少 命运决定在这里，我们将进行细胞和分子生物学分析，以阐明表达 神经节苷脂的模式，神经节苷脂在生长因子激活中的功能作用，以及神经节苷脂在生长因子激活中的作用机制。 在神经分化过程中调节糖基转移酶（GT）。总体目标将通过 具体有三个目的：1）研究神经节苷脂在神经干细胞中的表达， 与特定生长因子及其受体相关的特定神经节苷脂，用于调节NSC细胞命运 决定，如自我更新，增殖，分化，迁移和生存。完成这项工作的方法是 通过研究生长因子介导的细胞事件中的阶段特异性神经节苷脂， 基因敲除小鼠; 2）确定神经干细胞中GT表达的调控机制， 在分化过程中神经节苷脂表达的显著变化（“通路转换”）。特别是要 通过一种新的酶复合物形成机制研究GT表达的翻译后调节， 其生物合成的关键代谢分支点;和3）为了确定一种新的表观遗传调节因子， GT在神经元分化中的表达机制，特别是在出生后的神经发生中。我们将 测试核GM 1与神经元细胞中的基因调控相关的假设。自从GSL 表达谱不仅与正常发育有关，而且与肿瘤的致病机制有关。 疾病，拟议的研究将显着提高对GSL的功能作用的理解， 神经发生和阶段特异性GSL差异表达的分子机制。 这些信息将是非常有用的，在提供新的战略，疾病的治疗和神经 NSC的再生

Gangliosides are glycosylated sphingolipids with essential but enigmatic function in brain development and neural stem cell (NSC) maintenance. A critical barrier to our knowledge on ganglioside function in the brain is the absence of a systematic approach targeting key regulatory mechanisms in NSC differentiation instructed by gangliosides. Our group has pioneered research on the importance of gangliosides for growth factor receptor signaling and epigenetic regulation of NSCs. The overall goal of this project is to further elucidate the functional roles of gangliosides in NSCs based on contemporary concepts and technologies. The primary localization of glycosphingolipids (GSLs) on cell-surface microdomains and the drastic dose and composition changes during neural differentiation strongly suggest that GSLs are not only important as biomarkers but also are involved in modulating NSC functions. Many stage-specific GSL antigens in NSCs are now known, but less is understood about the mechanisms for their biological functions in modulating NSC cell fate determination. Here we will perform cellular and molecular biological analyses to elucidate the expression patterns of gangliosides, the functional roles of gangliosides in growth factor activation, and the mechanisms in regulating glycosyltransferases (GTs) during neural differentiation. The overall goal will be achieved by the following three specific aims: 1) To determine the expression of gangliosides in NSCs and the functional roles of specific gangliosides in relation to specific growth factors and their receptors for regulating NSC cell fate determination, such as self-renewal, proliferation, differentiation, migration, and survival. This will be achieved by investigation of stage-specific gangliosides in growth factor-mediated cellular events in normal and GT knockout mice; 2) To determine the regulatory mechanisms of GT expression in NSCs that account for the dramatic changes of ganglioside expression (“pathway switch”) during differentiation. In particular, we will study the post-translational regulation of GT expression by a novel enzyme complex formation mechanism at key metabolic branching points of their biosynthesis; and 3) To determine a novel epigenetic regulatory mechanism of GT expression in neuronal differentiation, particularly during postnatal neurogenesis. We will test the hypothesis that nuclear GM1 is associated with gene regulation in neuronal cells. Since GSL expression profiles are associated not only with normal development but also with pathogenic mechanisms of diseases, the proposed studies will significantly enhance the understanding of the functional role of GSLs in neurogenesis and the molecular mechanisms underlying the differential expression of stage-specific GSLs. This information will be extremely useful in providing novel strategies for disease treatment and neural regeneration by NSCs.