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Oligodendrocyte-microglia communication in the initiation of chronic secondary neuroinflammation

少突胶质细胞-小胶质细胞通讯在慢性继发性神经炎症启动中的作用

基本信息

批准号：
398078851
负责人：
Dr. Janos Groh
金额：
--
依托单位：
Neurologische Klinik und Poliklinik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/398078851?language=en
关键词：
Oligodendrocyte microglia communication initiation chronic

项目摘要

Genetically caused neurological disorders of the CNS usually lead to chronic disability, substantial decline in quality of life and are often not or poorly treatable. Many of them are accompanied by neuroinflammation of uncertain pathogenic relevance. Using a strategy allowing controlled insertion of two (proteolipid protein) PLP1 gene mutations previously described in human multiple sclerosis (MS) patients, we have generated mouse models reflecting several important aspects of chronic progressive multiple sclerosis (PMS) but also hereditary spastic paraplegia (HSP) including myelin abnormalities, axonal perturbation, neuron loss and moderate neuroinflammation. In favour of the hypothesis that primary oligodendroglial perturbation can trigger pathologically-relevant secondary neuroinflammation that drives neurodegeneration, genetic inactivation experiments unequivocally demonstrated a substantial disease-modifying impact of low-grade inflammation by adaptive immune cells in these models. The present proposal is aimed to identify molecular signals and cellular interactions of mutant oligodendrocytes and sialoadhesin-positive (Sn+) activated microglia that initiate and promote this detrimental secondary immune reaction in these newly generated mice in comparison with models for a PLP1-related leukodystrophy and a genetically unrelated neurodegenerative lysosomal storage disease also associated with early axonal damage and neuroinflammation. Identifying common and distinct inflammation-related disease pathways in these models will provide us with pathomechanistic insights as well as putative therapeutic targets for treatment of PMS and some genetically-mediated disorders of the nervous system accompanied by pathogenic neuroinflammation.

遗传引起的中枢神经系统神经紊乱通常会导致慢性残疾，生活质量大幅下降，而且往往无法或难以治疗。其中许多还伴有不确定病原相关性的神经炎症。使用一种策略，允许控制插入两个（蛋白脂蛋白）PLP1基因突变，先前在人类多发性硬化症（MS）患者中描述过，我们已经建立了小鼠模型，反映了慢性进行性多发性硬化症（PMS）和遗传性痉挛性截瘫（HSP）的几个重要方面，包括髓鞘异常，轴突摄动，神经元丢失和中度神经炎症。支持原发少突胶质细胞扰动可以触发病理相关的继发性神经炎症，从而驱动神经退行性变的假设，遗传失活实验明确证明了这些模型中适应性免疫细胞的低级别炎症具有实质性的疾病修饰作用。本研究旨在鉴定突变少突胶质细胞和唾液黏着素阳性（Sn+）激活的小胶质细胞的分子信号和细胞相互作用，这些细胞在这些新生小鼠中启动和促进这种有害的继发性免疫反应，并与plp1相关的白质营养不良和遗传无关的神经退行性溶酶体贮积病模型进行比较，这些模型也与早期轴突损伤和神经炎症相关。在这些模型中识别常见和独特的炎症相关疾病途径将为我们提供病理机制的见解以及治疗经前症候群和一些遗传介导的神经系统疾病伴随致病性神经炎症的假定治疗靶点。