Oligodendrocyte responses to stresses

项目概要 髓鞘形成对于神经系统的正常发育至关重要，幼年期是髓鞘形成的主要时期。 髓鞘形成期。少突胶质细胞（中枢神经系统的髓鞘形成细胞）的分化与 少突胶质细胞发育受到调节和破坏会导致神经系统问题，例如脑室周围 白细胞软化和发育迟缓。尽管人们对这一时期的损伤如何影响髓鞘形成知之甚少， 围产期或成人的缺血性损伤会损害少突胶质细胞和其他细胞，从而驱动 主要组织损伤。我们发起了研究来调查青少年缺血对中枢神经系统髓鞘形成的影响， 因为这个时期的代谢需求明显不同。我们发现尽管纹状体大量死亡 神经元、少突胶质细胞和有髓鞘轴突在幼年大脑中得到了显着的保存， 与成人相比，成人表现出广泛的少突胶质细胞和髓磷脂损伤（Ahrendsen 等人，Glia 64:1972, 2016）。非常有趣的是，除了少突胶质细胞对缺血性损伤的积极抵抗之外， 髓鞘形成的幼年大脑，一种在一生中持续活跃髓鞘形成的转基因小鼠品系，也具有 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 高水平的抗氧化途径分子可以保护它们免受缺血性损伤 损伤会增加胰岛素样生长因子 (IGF-1) 的表达，该因子在自分泌机制中发挥作用 方式额外保护髓鞘少突胶质细胞。我们有三个相关的具体目标来测试 这些假设通过研究 1) Nrf2 信号通路在主动髓鞘形成中的作用 少突胶质细胞对缺血的反应； 2）IGF-1在保护活跃髓鞘形成中的作用 少突胶质细胞； 3) IGF-1信号传导与活性氧结合在驱动中的作用 少突胶质细胞祖细胞分化。

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.