Glycolipids of Neural Stem Cells

神经干细胞的糖脂

• 批准号: 10062520
• 负责人: Robert K. YU
• 金额: $ 33.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062520
• 关键词: Adhesions; Adult; Affect; Anabolism; Antigens; Binding; Biological; Biological Markers; Biological Process; Brain; Cell Differentiation process; Cell Maintenance; Cell Proliferation; Cell membrane; Cell surface; Cells; Central Nervous System Diseases; Chromatin; Complex; Data; Development; Disease; Dose; Epigenetic Process; Event; Future; GD2 synthase; GD3-synthase; Ganglioside GM1; Gangliosides; Gene Expression Regulation; Genetic Diseases; Genetic Transcription; Glycolipids; Glycosphingolipids; Goals; Growth Factor; Growth Factor Receptors; Intraventricular Infusion; Investigation; Knockout Mice; Knowledge; Mediating; Metabolic; Molecular; Multienzyme Complexes; Mus; Mutation; Nerve Regeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Neurosciences; Nuclear; Outcome; Pathogenicity; Pathologic; Pathway interactions; Pattern; Play; Post-Translational Protein Processing; Post-Translational Regulation; Publishing; Receptor Signaling; Research; Role; Series; Signal Pathway; Signal Transduction; Sphingolipids; Surface; Technology; Testing; Undifferentiated; base; cell fate specification; cell type; dentate gyrus; differential expression; epigenetic regulation; glycosyltransferase; innovation; migration; nerve stem cell; nervous system development; neurogenesis; neuroregulation; novel; novel strategies; postnatal; receptor; relating to nervous system; repaired; self-renewal; stem cell differentiation; stem cell fate; stem cell fate specification; stem cell function; stem cell proliferation; stemness; subventricular zone; sugar

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.

神经节苷脂是一种糖基化的神经鞘糖脂，在脑发育中具有重要而神秘的功能。 和神经干细胞(NSC)的维持。我们对神经节苷脂功能了解的一个关键障碍 脑是缺乏针对神经干细胞分化的关键调控机制的系统方法 由神经节苷脂指导。我们的团队率先研究了神经节苷脂对生长的重要性 因子受体信号与神经干细胞的表观遗传调控。该项目的总体目标是进一步 根据当代概念和技术阐明神经节苷脂在神经干细胞中的功能作用。这个 鞘糖脂(GSLS)在细胞表面微区的初步定位及其强烈剂量和 神经分化过程中的成分变化强烈表明，GSLS不仅在 生物标志物也参与调节NSC的功能。神经干细胞中的许多阶段特异性GSL抗原是 目前已知，但对它们在调节NSC细胞中的生物学功能的机制了解较少 命运决定论。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作用及其机制 调节神经分化过程中的糖基转移酶(GTS)。总体目标将在以下时间实现 目的：1)确定神经节苷脂在神经干细胞中的表达及其功能 特定神经节苷脂与特定生长因子及其受体调控NSC细胞命运的关系 决心，如自我更新、增殖、分化、迁移和生存。这将会实现的 通过研究正常和GT中生长因子介导的细胞事件中的阶段特异性神经节苷脂 2)确定神经干细胞中GT表达的调节机制 分化过程中神经节苷脂表达的急剧变化(“通路开关”)。特别是，我们将 通过一种新的酶复合体形成机制研究翻译后对GT表达的调节 其生物合成的关键代谢分支点；3)确定新的表观遗传调控 GT在神经元分化中的表达机制，特别是在出生后神经发生过程中。我们会 检验核GM1与神经细胞基因调控相关的假设。自GSL以来 表达谱不仅与正常发育有关，而且与糖尿病的发病机制有关。 对于疾病，拟议的研究将显著增强对GSLS在 神经发生和阶段特异性GSLS差异表达的分子机制。 这些信息将对疾病治疗和神经治疗提供新的策略非常有用。 由神经干细胞再生。