Oligodendrocyte responses to stresses

项目摘要 髓鞘形成对于正常的神经系统发育是必不可少的，少年期是主要的 髓鞘形成期。少突胶质细胞（CNS的髓鞘形成细胞）的分化是紧密相关的。 少突胶质细胞发育的调节和破坏导致神经系统问题，如脑室周围 白质软化和发育迟缓。这一时期的损伤如何影响髓鞘形成尚不清楚，尽管 围产期或成年期的缺血性损伤损伤少突胶质细胞沿着其它细胞， 严重的组织损伤我们开始研究幼年缺血对CNS髓鞘形成的影响， 因为这一时期有着明显不同的代谢需求。我们发现，尽管纹状体细胞大量死亡， 神经元、少突胶质细胞和有髓轴突在幼年脑中明显保留，在stark 与表现出广泛的少突胶质细胞和髓磷脂损伤的成人相反（Ahrendsen等人，胶质 64：1972，2016）。非常有趣的是，除了少突胶质细胞对缺血性损伤的抵抗外， 髓鞘形成幼年脑，一个转基因小鼠品系，继续活跃的髓鞘形成整个生命也有 相对受保护的少突胶质细胞。 在拟议的研究中，我们将测试活跃的髓鞘形成少突胶质细胞具有 高水平的抗氧化途径分子，保护他们免受缺血性损伤， 损伤增加了胰岛素样生长因子（IGF-1）的表达，IGF-1在自分泌过程中起作用。 以额外保护髓鞘生成少突胶质细胞的方式。我们有三个相关的具体目标， 这些假设通过研究1）Nrf 2信号通路在活跃髓鞘形成中的作用， 2）IGF-1在保护少突胶质细胞活性髓鞘形成中的作用 少突胶质细胞;和3）IGF-1信号转导与活性氧在驱动中的作用 少突胶质祖细胞分化。

Project Summary Myelination is essential for normal nervous system development, and the juvenile period is a major period of myelination. Differentiation of the oligodendrocyte, the myelinating cell of the CNS, is tightly regulated, and disruption of oligodendrocyte development leads to neurologic problems, such as periventricular leukomalacia and retardation. How injury during this period impacts myelination is poorly understood, although ischemic damage in the perinatal period or adults damages oligodendrocytes along with other cells, driving major tissue damage. We initiated studies to investigate the impact of juvenile ischemia on CNS myelination, as this period has distinctly different metabolic demands. We found that despite extensive death of striatal neurons, oligodendrocytes and myelinated axons were remarkably preserved in the juvenile brain, in stark contrast to the adult which exhibits extensive oligodendrocyte and myelin injury (Ahrendsen et al., Glia 64:1972, 2016). Quite intriguingly, in addition to oligodendrocyte resistance to ischemic injury in the actively myelinating juvenile brain, a transgenic mouse line that continues active myelination throughout life also has relatively protected oligodendrocytes. In the proposed studies, we will test the hypotheses that actively myelinating oligodendrocytes have high levels of anti-oxidant pathway molecules that protect them from ischemic damage, and that such damage increases their expression of insulin-like growth factor (IGF-1), which acts in an autocrine m manner to additionally protect myelinating oligodendrocytes. We have three related specific aims that test these hypotheses by investigating 1) the role of the Nrf2 signaling pathway in actively myelinating oligodendrocytes in response to ischemia; 2) the role of IGF-1 in protection of actively myelinating oligodendrocytes; and 3) the role of IGF-1 signaling in conjunction with reactive oxygen species in driving oligodendrocyte progenitor cell differentiation.