Development of myelinating oligodendrocytes in Down syndrome

唐氏综合征(DS)可能导致智力残疾的发育事件清单包括 单个基因的过度表达改变了神经细胞的突触和放电特性 系统。最近，我们实验室发现了少突胶质前体细胞(OPC)的固有缺陷。 在DS小鼠模型中，成熟导致髓鞘形成和白质束形成的变化。这 利用人脑基因表达谱和髓鞘成像证实了髓鞘功能障碍 延长动作电位到达突触后靶点所需的时间。因为这个新奇的细胞 缺陷可能是DS患者至少部分智力障碍的基础，这是一种直接的治疗方法 方法是用促进OPC成熟的化合物进行治疗。鼠标模型中的初步结果 很有希望，但患有DS的人类OPC是否表现出与小鼠模型细胞相同的缺陷 对这一努力至关重要。 在这个项目中，我们将利用现有的人类干细胞系和快速的OPC编程 首次评估人DS来源的OPC的成熟度。接下来，在一系列体外试验中 实验，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髓磷脂缺乏的颤抖小鼠的大脑中，他们的髓鞘形成潜力。这个 这些研究的结果将为DS领域的未来研究产生一种新的细胞资源，测试 假设人类DS来源的OPC表现出与小鼠模型细胞相同的缺陷，并评估 两种可用于改善DS患者大脑髓鞘形成的潜在药物的疗效。

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.