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NG2-expressing cells in demyelination and remyelination: studies using new transgenic mouse models

脱髓鞘和髓鞘再生中表达 NG2 的细胞：使用新转基因小鼠模型的研究

基本信息

批准号：
103728416
负责人：
Professorin Dr. Jacqueline Trotter, Ph.D.
金额：
--
依托单位：
Institut für Entwicklungsbiologie und Neurobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/103728416?language=en
关键词：
NG2 expressing cells demyelination remyelination

项目摘要

In this proposal we plan to generate demyelinating lesions using novel transgenic mouse strains. Although early phases of MS and most demyelinating animal models exhibit considerable remyelination, in later phases of the disease remyelination fails leading to irreversible axonal pathology. Remyelination in animal models has been shown to be carried out by surviving mitotic oligodendrocyte progenitor cells (OPC). OPC cells express the NG2 proteoglycan: we have recently generated a transgenic mouse line in which the EYFP gene is inserted in the first exon of the endogeneous NG2 gene, resulting in yellow cells in the CNS when the endogeneous promotor is active thus enabling study of the behaviour of NG2 cells in development as well as in lesions. The lab of Ari Waisman has generated a mouse line in which MOG-expressing oligodendrocytes are deleted after injection of mice with diptheria toxin (MOG-iCre-iDTR mice). In this project we plan to cross these two mouse strains to allow us to induce demyelinating lesions in mice in which NG2–expressing cells are labelled. We will address how NG2+ progenitor cells interact with demyelinated axons, the characteristics of these cells and whether continual cycles of demyelination result in progenitor cell depletion. By generating autoantibodies specific for NG2 via DNA vaccination, we will investigate whether mounting an immune response against the progenitor cells in vivo results in an exacerbation of remyelination due to deletion, or blockage of migration of the OPC. Lastly, we will cross the homozygous NG2- EYFP mice, which are null mutants for NG2 with the MOG-iCreiDTR heterozygous mice, to determine whether the lack of the NG2 protein affects remyelination.

在这个提议中，我们计划使用新的转基因小鼠品系产生脱髓鞘病变。尽管MS的早期阶段和大多数脱髓鞘动物模型表现出相当大的髓鞘再生，但在疾病的后期阶段，髓鞘再生失败，导致不可逆的轴突病理学。动物模型中的再髓鞘化已被证明是由存活的有丝分裂少突胶质细胞祖细胞（OPC）进行的。OPC细胞表达NG 2蛋白聚糖：我们最近产生了一种转基因小鼠系，其中EYFP基因插入内源性NG 2基因的第一个外显子中，当内源性启动子激活时，导致CNS中的黄色细胞，从而能够研究NG 2细胞在发育和病变中的行为。Ari Waisman的实验室已经产生了一种小鼠品系，其中MOG表达少突胶质细胞在注射白喉毒素后被删除（MOG-iCre-iDTR小鼠）。在这个项目中，我们计划将这两种小鼠品系杂交，使我们能够在标记NG 2表达细胞的小鼠中诱导脱髓鞘病变。我们将讨论NG 2+祖细胞如何与脱髓鞘轴突相互作用，这些细胞的特征以及脱髓鞘的持续循环是否会导致祖细胞耗竭。通过DNA疫苗接种产生NG 2特异性自身抗体，我们将研究体内针对祖细胞的免疫应答是否会导致由于OPC缺失或迁移阻断而导致髓鞘再生恶化。最后，我们将纯合NG 2- EYFP小鼠（其是NG 2的无效突变体）与MOG-iCreiDTR杂合小鼠杂交，以确定NG 2蛋白的缺乏是否影响髓鞘再生。