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

项目摘要/摘要 神经发育需要神经干细胞有控制的自我更新和分化。失调症 神经干细胞相关的通路发生在许多神经病理中，甚至当方向改变或基因 变化是明显的。我们发现，正常和肿瘤神经干细胞表达ST6Gal1，这是一种主要的酶 2，6-唾液酸化N-糖基化的蛋白质，运往细胞表面。在我们的理解上有严重的差距 ST6Gal1介导的唾液酸化如何影响细胞信号以调节神经发育、脑老化、 神经退行性变，或胶质瘤形成。填补这些空白并进一步研究其功能和分子靶点 对于大脑中的ST6Gal1和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ST6Gal1的表达上调。我们试图刻画ST6Gal1在细胞中的表达 现有的小鼠模型随着时间的推移和确定ST6Gal1介导的2，6唾液酸化对正常和 体内肿瘤神经干细胞库。短期内，这些研究将阐明ST6Gal1和ST6Gal1的影响 发育中的大脑和神经胶质瘤中的唾液酸化。一旦表征，独特的模式将是一个宝贵的 神经科学和神经肿瘤学社区的资源，以确定ST6Gal1的神经病理作用- 介导的2，6唾液酸化反应。

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.