The role of Endothelin-1 in oligodendrocyte development and regeneration

项目总结 该应用侧重于研究室下区(SVZ)中调节少突胶质细胞的信号 (Ol)健康和受伤的大脑的发育。OL起源于SVZ中的神经干细胞，并产生 髓鞘隔离神经元轴突的髓鞘，从而允许适当的突触传递。损坏或 OL的丢失会导致许多神经问题，如多发性硬化症和其他 神经退行性疾病。因此，确定调节OL发育的内源性机制 体内修复可能会为治疗此类疾病带来新的治疗靶点。我们之前的研究发现 在啮齿动物白质脱髓鞘后，信号肽-内皮素-1延缓了OL的成熟 大脑。这表明内皮素-1是体内OL发育的一种新的调节因子。为了检验这一假设， 内皮素-1在正常发育和白质损伤后的SVZ中的作用 下定决心。首先，对出生后SVZ中内皮素-1的机制进行遗传学解剖。 条件性基因敲除小鼠和RNA测序。然后，利用溶血磷脂模型进行脱髓鞘和病毒 追踪，将确定SVZ衍生的内皮素-1在OL再生中的作用。

PROJECT SUMMARY This application focuses on investigating signals in the subventricular zone (SVZ) that regulate oligodendrocyte (OL) development in the healthy and injured brain. OLs arise from neural stem cells in the SVZ and produce the myelin sheaths that insulate neuronal axons, thus allowing proper synaptic transmission. Damage to or loss of OLs results in many neurological problems, as can be seen in multiple sclerosis and other neurodegenerative diseases. Therefore, identifying endogenous mechanisms that regulate OL development and repair in vivo may lead to new therapeutic targets for treating such conditions. Our previous studies found that the signaling peptide, Endothelin-1, delays OL maturation after demyelination of white matter in the rodent brain. This suggests that Endothelin-1 is a novel regulator of OL development in vivo. To test this hypothesis, the function of Endothelin-1 in the SVZ during normal development and after white matter injury will be determined. First, the mechanism of Endothelin-1 in the postnatal SVZ will be genetically dissected using conditional knockout mice and RNA sequencing. Then, using the lysolecithin model of demyelination and viral tracing, the role of SVZ-derived Endothelin-1 in OL regeneration will be defined.