The role of Endothelin-1 in oligodendrocyte development and regeneration

项目摘要 本申请的重点是调查信号室管膜下区（SVZ），调节少突胶质细胞 (OL)在健康和受伤的大脑中的发展。OL来自SVZ中的神经干细胞， 隔离神经元轴突的髓鞘，从而允许正确的突触传递。损坏或 OL的丧失导致许多神经问题，如在多发性硬化症和其他疾病中可以看到的。 神经退行性疾病因此，确定调节OL发育的内源性机制， 并且体内修复可能导致治疗这些病症的新的治疗靶点。我们之前的研究发现 在啮齿类动物中，信号肽内皮素-1延迟了白色物质脱髓鞘后的OL成熟 个脑袋这表明内皮素-1是体内OL发育的新调节剂。为了验证这个假设， 内皮素-1在正常发育期间和白色物质损伤后SVZ中的功能将被 测定首先，内皮素-1在出生后SVZ中的机制将通过使用 条件敲除小鼠和RNA测序。然后，使用脱髓鞘和病毒的溶血素模型， 通过追踪，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.