Development of myelinating oligodendrocytes in Down syndrome

可能导致唐氏综合征（DS）智力残疾的发育事件列表包括 单个基因的过度表达改变了神经元的突触和放电特性， 系统近年来，本实验室发现少突胶质细胞前体细胞（OPC）存在内在缺陷 成熟，导致髓鞘形成和白色物质束形成的变化。这 使用人脑基因表达谱和髓鞘成像证实的髓鞘形成障碍已经显示， 延长动作电位到达突触后靶点的时间。由于这种新型的细胞 一个缺陷可能是DS中至少部分智力残疾的基础，DS是一种直接的治疗方法， 方法将是用促进OPC成熟的化合物治疗。小鼠模型的初步结果 有希望，但来自DS患者的OPCs是否表现出与小鼠模型细胞相同的缺陷， 这一努力至关重要。 在这个项目中，我们将利用预先存在的人类干细胞系和快速OPC编程 第一次评估人DS衍生的OPCs成熟的方案。接下来，在一系列的体外实验中， 在实验中，我们将测试两种FDA批准的药物促进OPC分化的能力，然后测试 通过将这些细胞移植到缺乏髓鞘的Shiverer小鼠脑中，的 这些研究的结果将为DS领域的未来研究产生一种新的蜂窝资源，测试 假设人DS衍生的OPCs表现出与小鼠模型细胞中发现的相同缺陷，并评估 两种潜在药物的功效，可用于改善患有DS的人大脑中的髓鞘形成。

The list of developmental events that may lead to intellectual disability in Down syndrome (DS) ranges from the over expression of single genes to altered synaptic and firing properties of neurons throughout the nervous system. Recently, our laboratory has discovered intrinsic defects in oligodendrocyte precursor cell (OPC) maturation that lead to changes in myelination and white matter tract formation in a mouse model of DS. This dysmyelination, confirmed using human brain gene expression profiling and myelin imaging, has been shown to lengthen the time it takes for action potentials to reach their postsynaptic targets. Since this novel cellular defect presumably underlies at least part of the intellectual disability in DS, a straightforward therapeutic approach would be to treat with compounds that promote OPC maturation. Initial results in mouse models look promising, but whether OPCs from humans with DS exhibit the same defects found in mouse model cells is critical for this effort. In this project, we will take advantage of pre-existing human stem cell lines and rapid OPC programming protocols to evaluate the maturation of human DS-derived OPCs for the first time. Next, in a series of in vitro experiments, we will test two FDA-approved drugs for their ability to prompt OPC differentiation and then test their myelination potential by transplanting these cells into the myelin-deficient Shiverer mouse brain. The results of these studies will generate a novel cellular resource for future study in the DS field, test the hypothesis that human DS-derived OPCs exhibit the same defects found in mouse model cells, and evaluate the efficacy of two potential drugs that could be used to improve myelination in the brains of people with DS.