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Regulation of Microglial Activation State by a Lipid Transporter

Regulation of Microglial Activation State by a Lipid Transporter
脂质转运蛋白对小胶质细胞激活状态的调节
批准号:
10112795
负责人:
Erhard Bieberich
金额:
$37.51万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-03-01 至 2024-12-31

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中文摘要
翻译
摘要 功能性基因组关联研究表明,失调的小胶质细胞激活 是阿尔茨海默病神经退行性变和认知能力下降的主要促成因素 (AD)。因此,调节小胶质细胞的激活状态可能具有深远的治疗潜力, AD.然而,小胶质细胞在不同状态之间转换的潜在机制 在正常和疾病条件下,大部分是未知的。S1 P信号转导与 在AD中扮演重要角色。然而,S1 P在AD中的功能尚不清楚,由于相互矛盾的报告。 一方面,死后AD患者脑中S1 P水平降低,表明AD患者脑中S1 P水平降低。 S1 P的保护作用另一方面,也有报道称,S1 P可能会发挥 相反虽然已经在Aβ相关AD小鼠模型中进行了测试,但FTY 720在AD中的作用仍然是未知的。 tau病理学是难以捉摸的。此外,FTY 720可以根据细胞特性而具有不同的功能。 背景和处理程序,这使得解释S1 P的作用具有挑战性。因此 AD中S1 P信令的功能比假设的更复杂,需要进一步研究 我们的初步研究表明,Spinster同源物2(Spns 2),一种S1 P转运蛋白, 调节小胶质细胞从炎症状态向抗炎状态的转变, Aβ肽。这些数据很有趣,因为它揭示了小胶质细胞状态可以通过 Spns 2和/或S1 P。由于小胶质细胞是中枢神经系统免疫防御的第一道也是主要的防线, 在神经系统中,我们将主要研究Spns 2在小胶质细胞激活中的作用。 应用程序.星形胶质细胞,其他主要的神经胶质细胞类型,和其他S1 P转运蛋白的作用, 作为ABCA 1,也将进行评估。我们的目标是定义功能和基本机制 Spns 2在AD小胶质细胞反应中的作用。我们的目标是定义函数和底层 Spns 2在AD小胶质细胞反应中的作用机制我们的首要假设是Spns 2 通过促进小胶质细胞的促炎性激活, AD相关刺激。我们将测试(1)Spns 2增强小胶质细胞中的促炎反应 (2)Spns 2/S1 P促进NFκB和p38 MAPK的促炎作用 小胶质细胞中Aβ和tau蛋白诱导的信号传导,以及(3)Spns 2缺陷改善AD相关的 小鼠AD模型中的表型。通过关注S1 P转运蛋白Spns 2,该提议成立 一个独特的前提,揭示新的方面S1 P信号在AD发病机制。
英文摘要
Abstract Functional genome wide association studies have indicated that dysregulated microglia activation is a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease (AD). Thus, regulating the microglia activation state could have profound therapeutic potential for AD. However, the underlying mechanisms by which microglia transition between different states during normal and disease conditions are largely unknown. S1P-signaling has been implicated to play important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports. On one hand, the level of S1P is reduced in postmortem AD patient brains, suggesting a protective role of S1P. On the other hand, there are also reports indicating that S1P might play the opposite. Although has been tested in Aβ-related AD mouse models, the role of FTY720 in tau pathology is elusive. Further, FTY720 can have different function depending on the cellular context and treatment procedure, which makes interpretation of S1P's role challenging. Thus, the function of S1P-signaling in AD is more complex than assumed and demands further investigation Our preliminary studies suggest that Spinster homolog 2 (Spns2), an S1P transporter, critically modulates microglial transition from inflammatory to anti-inflammatory states when treated with Aβ peptide. This data is interesting in that it reveals microglia states could be regulated through Spns2 and/or S1P. Since microglia form the first and major line of immune defense in the central nervous system, we will mainly investigate the function of Spns2 on microglia activation in this application. The role of astrocytes, the other major glial cell type, and other S1P transporters such as ABCA1, will also be evaluated. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our overarching hypothesis is that Spns2 contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced by AD-related stimuli. We will Test that (1) Spns2 enhances pro-inflammatory responses in microglia induced by AD-related stimuli, (2) Spns2/S1P promotes NFκB and p38 MAPK pro-inflammatory signaling induced by Aβ and tau in microglia, and (3) Spns2 deficiency ameliorates AD-related phenotypes in murine AD models. By focusing on the S1P transporter Spns2, this proposal holds a unique premise to reveal novel aspects of S1P-signaling in AD pathogenesis.
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Novel experimental models to study the effect of extracellular vesicles on neurons
  • 批准号:
    10508346
  • 项目类别:
  • 资助金额:
    $42.08万
  • 财政年份:
    2022
  • 负责人:
    Erhard Bieberich
  • 依托单位:
Regulation of Microglial Activation State by a Lipid Transporter
  • 批准号:
    9887304
  • 项目类别:
  • 资助金额:
    $37.53万
  • 财政年份:
    2020
  • 负责人:
    Erhard Bieberich
  • 依托单位:
Regulation of Microglial Activation State by a Lipid Transporter
  • 批准号:
    10536663
  • 项目类别:
  • 资助金额:
    $37.46万
  • 财政年份:
    2020
  • 负责人:
    Erhard Bieberich
  • 依托单位:
TBI-induced exosome release accelerates Alzheimer's disease pathology
海外基金