Novel Mouse Models to Understand ST6Gal1-Mediated Sialylation Effects in the Developing and Pathologic Brain

项目概要/摘要 神经发育需要神经干细胞的受控自我更新和分化。失调 神经干细胞相关通路发生在许多神经病理学中，即使当改变的方向或遗传 变化是不同的。我们发现正常和肿瘤神经干细胞表达ST 6 Gal 1， α 2，6唾液酸化N-糖基化蛋白质，使其到达细胞表面。在我们的理解中存在着严重的差距 ST 6 Gal 1介导的唾液酸化如何影响细胞信号传导以调节神经发育，大脑衰老， 神经变性或胶质瘤形成。为了填补这些空白，并进一步研究功能和分子靶点， 的ST 6 Gal 1和α 2，6唾液酸化，我们产生了两个新的小鼠模型，允许空间和时间 星形胶质细胞和神经干细胞中ST 6 Gal 1的升高。我们试图表征ST 6 Gal 1在 现有的小鼠模型，并确定ST 6 Gal 1介导的α 2，6唾液酸化对正常和 体内肿瘤性神经干细胞库。在短期内，这些研究将阐明ST 6 Gal 1的影响， 唾液酸化在发育中的大脑和神经胶质瘤中的作用。一旦特征化，独特的模型将是一个有价值的 神经科学和神经肿瘤学社区的资源，以确定ST 6 Gal 1的神经病理学作用- 介导的α 2，6唾液酸化。

PROJECT SUMMARY/ABSTRACT Neurodevelopment requires the controlled self-renewal and differentiation of neural stem cells. Dysregulation of neural stem cell-related pathways occurs in many neuropathologies, even when the direction of change or genetic alterations are distinct. We find that normal and neoplastic neural stem cells express ST6Gal1, the primary enzyme that a2,6 sialylates N-glycosylated proteins destined for the cell surface. There are critical gaps in our understanding of how ST6Gal1-mediated sialylation could impact cell signaling to regulate neurodevelopment, brain aging, neurodegeneration, or gliomagenesis. To fill these gaps and further investigate the function and molecular targets of ST6Gal1 and a2,6 sialylation in the brain, we generated two novel mouse models that permit spatial and temporal elevation of ST6Gal1 in astrocytes and neural stem cells. We seek to characterize the expression of ST6Gal1 in the existing mouse models over time and determine effects of ST6Gal1-mediated a2,6 sialylation on the normal and neoplastic neural stem cell pool in vivo. In the short-term, these studies will elucidate impacts of ST6Gal1 and sialylation in the developing brain and in gliomagenesis. Once characterized, the unique models will be a valuable resource for the neuroscience and neuro-oncology communities to identify neuropathological roles for ST6Gal1- mediated a2,6 sialylation.