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，即使改变方向或遗传 变化是明显的。我们发现正常和肿瘤神经干细胞表达 ST6Gal1，这是主要的酶 a2,6 唾液酸化去往细胞表面的 N-糖基化蛋白质。我们的理解存在严重差距 ST6Gal1 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，或神经胶质瘤发生。填补这些空白并进一步研究其功能和分子靶点 为了研究大脑中 ST6Gal1 和 a2,6 唾液酸化的情况，我们生成了两种新颖的小鼠模型，它们允许空间和时间 星形胶质细胞和神经干细胞中 ST6Gal1 的升高。我们试图表征 ST6Gal1 的表达 随着时间的推移现有的小鼠模型，并确定 ST6Gal1 介导的 a2,6 唾液酸化对正常和 体内肿瘤神经干细胞池。在短期内，这些研究将阐明 ST6Gal1 和 发育中的大脑和神经胶质瘤发生中的唾液酸化。一旦特征化，独特的模型将是有价值的 神经科学和神经肿瘤学界的资源，以确定 ST6Gal1- 的神经病理学作用 介导的a2,6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.