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中文摘要
翻译
星形胶质细胞在大脑中发挥着重要的生理功能。然而,为了应对各种 当受到损伤时,星形胶质细胞变得具有反应性并有助于恢复体内平衡。他们的反应也可以 在慢性炎症和脑肿瘤中观察到的病理性变化。反应性星形胶质细胞(RA) 他们的反应最近被认为是微环境中的关键角色, 原发性和转移性脑肿瘤最近,具有活化的STAT 3的RA子集具有以下特征: 已被证明对支持脑转移病灶的生长以及 胶质母细胞瘤细胞(GBM)。虽然RA中STAT 3的激活支持GBM细胞的生长, 在RA中驱动STAT 3激活的机制仍然是难以捉摸的。当过多的细胞因子和 生长因子诱导时间STAT 3活化,一种生物活性鞘脂,鞘氨醇-1- 磷酸盐(S1 P)可以通过其G蛋白偶联受体1驱动STAT 3的持续激活 (S1PR1)。S1 PR 1在星形胶质细胞中高度表达,并且在星形胶质细胞中缺失S1 PR 1限制了 它们的反应性,而鞘氨醇激酶1产生S1 P在GBM中过表达。这些 研究结果提出了一种可能性,即GBM衍生的S1 P通过激活RA中的STAT 3, S1 P/S1 PR 1/STAT 3轴。然而,研究RA机制的主要障碍是 激活是缺乏适当的胶质瘤模型,将允许遗传操作 特别是在这些细胞中。我们最近进一步发展了一个以前建立的 自发小鼠胶质瘤模型,这将使我们能够测试基因在RA中的重要性。我们 将检验我们的模型对研究RA的有用性,并测试S1 P/S1 PR 1/STAT 3是否 轴驱动基因表达程序,重新布线RA,导致建立一个 免疫抑制状态。我们还将确定S1 PR 1抑制是否影响 预先建立的神经胶质瘤
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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