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中文摘要
翻译
星形胶质细胞在大脑中发挥着关键的生理功能。然而,为了应对多样化的 如果受到侮辱,星形胶质细胞就会变得有反应,并帮助恢复体内平衡。他们的反应也可以 在慢性炎症和脑肿瘤中观察到的病理改变。反应性星形胶质细胞 他们的反应最近被认为是微环境中的关键角色 包括原发和转移性脑瘤。最近,激活了STAT3的RA的子集 已被证明对支持脑转移瘤的生长以及 胶质母细胞瘤细胞(GBM)。尽管RA中STAT3的激活支持GBM细胞的生长, 在RA中驱动STAT3激活的机制仍然难以捉摸。而过多的细胞因子和 生长因子诱导暂时的STAT3激活,一种生物活性的鞘磷脂,鞘氨醇-1- 磷酸(S1P)可通过其G蛋白偶联受体1驱动STAT3的持续激活 (S1PR1)。S1PR1在星形胶质细胞中高表达,S1PR1在星形胶质细胞中的缺失受到限制 它们的反应性,而鞘氨醇激酶1产生的S1P在GBM中过表达。这些 研究结果提出了一种可能性,即GBM来源的S1P通过 S1P/S1PR1/STAT3轴。然而,RA发病机制研究的主要障碍是 激活是缺乏适当的胶质瘤模型,可以进行基因操作 尤其是在这些细胞中。我们最近进一步开发了以前建立的 自发性小鼠胶质瘤模型,这将使我们能够测试基因在RA中的重要性。我们 我们将检验我们的模型对研究RA的有用性,并测试S1P/S1PR1/STAT3 Axis驱动基因表达计划,重新连接RA,从而建立 免疫抑制状态。我们还将确定S1PR1抑制是否会影响 预先形成的神经胶质瘤。
英文摘要
Astrocytes play critical physiological functions in the brain. However, in response to diverse insults, astrocytes become reactive and help to restore homeostasis. Their responses can also turn pathological as observed in chronic inflammation and brain tumors. Reactive astrocytes (RA) and their responses have recently been recognized as key players in the microenvironment of both primary and metastatic brain tumors. Recently a subset of RA with activated STAT3 has been shown to be critical for supporting growth of both brain metastatic lesions as well as glioblastoma cells (GBM). Although activation of STAT3 in RA supports the growth of GBM cells, mechanisms that drive STAT3 activation in RA remain elusive. While a plethora of cytokines and growth factors induce temporal STAT3 activation, a bioactive sphingolipid, sphingosine-1- phosphate (S1P) can drive persistent activation of STAT3 via its G-protein-coupled receptor 1 (S1PR1). S1PR1 is highly expressed by astrocytes, and deletion of S1PR1 in astrocytes limits their reactivity, while sphingosine kinase 1 generating S1P is overexpressed in GBM. These findings raise a possibility that GBM-derived S1P activates STAT3 in RA via the S1P/S1PR1/STAT3 axis. Nevertheless, the major obstacle in studying the mechanisms of RA activation is the lack of appropriate glioma model that would allow genetic manipulation specifically in these cells. We have recently further developed a previously established spontaneous mouse glioma model, which will allow us to test the importance of genes in RA. We will examine the usefulness of our model to study RA, and test whether the S1P/S1PR1/STAT3 axis drives gene expression programs that re-wire RA leading to establishment of an immunosuppressive state. We will also determine whether S1PR1 inhibition affects preestablished gliomas.
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DOI: 10.3390/cells10071609
发表时间: 2021-06-27
期刊: Cells
影响因子: 6
作者: [Mockenhaupt K, Gonsiewski A, Kordula T]
通讯作者: Kordula T
Regulation of astrocyte diversity in the cerebellum
  • 批准号:
    10659171
  • 项目类别:
  • 资助金额:
    $46.03万
  • 财政年份:
    2021
  • 负责人:
    TOMASZ K KORDULA
  • 依托单位:
Regulation of astrocyte diversity in the cerebellum
  • 批准号:
    10454433
  • 项目类别:
  • 资助金额:
    $46.03万
  • 财政年份:
    2021
  • 负责人:
    TOMASZ K KORDULA
  • 依托单位:
Regulation of astrocyte diversity in the cerebellum
  • 批准号:
    10278047
  • 项目类别:
  • 资助金额:
    $46.03万
  • 财政年份:
    2021
  • 负责人:
    TOMASZ K KORDULA
  • 依托单位:
Ying Yang 1, a master regulator of chronic inflammation in glioblastoma multiforme
  • 批准号:
    9515458
  • 项目类别:
  • 资助金额:
    $19.38万
  • 财政年份:
    2018
  • 负责人:
    TOMASZ K KORDULA
  • 依托单位:
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