Oligodendrocyte responses to stresses

项目摘要 髓鞘形成对神经系统的正常发育是必不可少的，青少年时期是 髓鞘形成时期。少突胶质细胞是中枢神经系统的髓鞘细胞，分化紧密。 少突胶质细胞发育的调节和中断会导致神经问题，如脑室周围 脑白质软化和发育迟缓。这一时期的损伤如何影响髓鞘形成还知之甚少，尽管 围产期或成人的缺血性损害与其他细胞一起损害少突胶质细胞， 严重的组织损伤。我们开始研究幼年缺血对中枢神经系统髓鞘形成的影响。 因为这个时期有明显不同的新陈代谢需求。我们发现，尽管纹状体广泛死亡 在斯塔克的幼年脑中，神经元、少突胶质细胞和有髓轴突显著保存。 与成体表现出广泛的少突胶质细胞和髓鞘损伤形成对比(Ahrendsen等人，Glia ：1972年，2016年)。相当耐人寻味的是，除了少突胶质细胞对缺血性损伤的抵抗外， 髓鞘幼年脑，一种在一生中持续活跃的髓鞘形成的转基因小鼠系也有 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少突胶质细胞具有的假设 保护它们免受缺血损伤的高水平抗氧化途径分子，以及这样的 损伤增加了胰岛素样生长因子(IGF-1)的表达，IGF-1在自分泌过程中发挥作用 额外保护髓鞘少突胶质细胞的方式。我们有三个相关的具体目标来测试 这些假说是通过研究1)Nrf2信号通路在主动髓鞘形成中的作用而得出的 少突胶质细胞对缺血的反应；2)IGF-1在保护主动髓鞘形成中的作用 少突胶质细胞；3)IGF-1信号与活性氧结合在驾驶中的作用 少突胶质细胞前体细胞分化。

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.