Prenatal inflammation disrupts blood-brain barrier development and long-term function.

产前炎症会破坏血脑屏障的发育和长期功能。

基本信息

  • 批准号:
    10594374
  • 负责人:
  • 金额:
    $ 39.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-01 至 2027-11-30
  • 项目状态:
    未结题

项目摘要

SUMMARY Maternal immune activation (MIA) during fetal development increases risk for neurodevelopmental disorders (NDDs) later in the offspring life. Chronic microglial activation in the adult offspring exposed to gestational MIA leads to a range of altered behaviors. Yet, the developmental mechanisms whereby MIA induces this sustained activation of offspring brain microglia across the lifespan are not understood. Systemic inflammation triggered during adulthood was shown to disrupt blood-brain barrier (BBB) function, inducing microglial activation, neuroinflammation and leading to the progressive emergence of neuropathologies. Even though comparable outcomes are observed in adult offspring who experienced gestational MIA, whether there is similar BBB disruption and the mechanisms leading to these phenotypes in utero are not known. This is an important knowledge gap because MIA is a risk factor for NNDs and there is growing evidence of vascular dysfunction contributing to the molecular pathology of these disorders. The investigators obtained preliminary data showing that MIA triggered by the viral mimetic poly(I:C) in pregnant mice disrupts fetal BBB formation leading to increased nascent BBB permeability measured using live fetal MRI. Their data further suggest that activation of the cyclooxygenase-2 (COX2; Ptgs2) pathway in fetal brain microglia is causal to MIA effects. Importantly, longitudinal MRI analyses suggest that disruption of fetal BBB formation induces persistent BBB hyperpermeability and life-long brain microglial activation, cerebrovascular inflammation, and behavioral alterations in the offspring. Through the combined expertises of four different research groups, the investigators developed and validated new methods for measuring fetal brain BBB permeability in vivo (MRI) and ex vivo (whole fetus perfusion) which, together with conditional knockout mouse lines, will be used to test: 1) if and how MIA activation of the COX2 pathway in fetal microglia perturbs fetal BBB formation at a critical time of development, leading to incomplete maturation, and 2) if and how the resulting protracted activation of COX2 pathway in resident microglia prolongs BBB structural disruption and neuroinflammation over the offspring lifespan. This self- perpetuating cycle of brain inflammation and BBB disruption would ultimately promote increased risk for neuropathology in the offspring. From an etiological standpoint, this pre-clinical proposal will define novel cellular and molecular pathways involved in life-long effects of prenatal insults, shedding light on the mechanisms by which early inflammation is causally linked to vascular disruptions in neurodevelopmental disorders.
概括 胎儿发育过程中母体免疫激活(MIA)会增加神经发育障碍的风险 (NDD)在后代生活的后期。暴露于妊娠 MIA 的成年后代的慢性小胶质细胞激活 导致一系列行为改变。然而,MIA 诱导这种持续的发育机制 后代大脑小胶质细胞在整个生命周期中的激活尚不清楚。引发全身炎症 在成年期被证明会破坏血脑屏障(BBB)功能,诱导小胶质细胞激活, 神经炎症并导致神经病理学的逐渐出现。即使有可比性 在经历妊娠 MIA 的成年后代中观察结果,是否存在类似的 BBB 子宫内的破坏和导致这些表型的机制尚不清楚。这是一个重要的 知识差距,因为 MIA 是 NND 的危险因素,并且越来越多的证据表明血管功能障碍 有助于这些疾病的分子病理学。 研究人员获得的初步数据显示,妊娠期病毒模拟聚(I:C)引发 MIA 小鼠破坏胎儿 BBB 形成,导致使用活体胎儿 MRI 测量的新生 BBB 通透性增加。 他们的数据进一步表明,胎儿脑小胶质细胞中环氧合酶 2 (COX2;Ptgs2) 通路的激活 是 MIA 效应的因果关系。重要的是,纵向 MRI 分析表明胎儿 BBB 形成受到破坏 诱导持续性 BBB 通透性过高和终生脑小胶质细胞激活、脑血管炎症、 以及后代行为的改变。 通过四个不同研究小组的综合专业知识,研究人员开发并 验证了体内 (MRI) 和离体 (整个胎儿) 测量胎儿脑 BBB 通透性的新方法 灌注),与条件敲除小鼠系一起,将用于测试:1)是否以及如何激活 MIA 胎儿小胶质细胞中 COX2 通路的变化会扰乱胎儿发育关键时期的 BBB 形成,从而导致 不完全成熟,以及 2) 是否以及如何导致驻留体内 COX2 通路的长期激活 小胶质细胞会延长后代寿命中的血脑屏障结构破坏和神经炎症。这个自 脑部炎症和血脑屏障破坏的持续循环最终将导致罹患此病的风险增加 后代的神经病理学。从病因学的角度来看,这一临床前提案将定义新的细胞 以及涉及产前侮辱终身影响的分子途径,揭示了其机制 早期炎症与神经发育障碍中的血管破坏有因果关系。

项目成果

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Alexandre Bonnin其他文献

Alexandre Bonnin的其他文献

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{{ truncateString('Alexandre Bonnin', 18)}}的其他基金

Prenatal stress and antidepressants effects on offspring brain development
产前压力和抗抑郁药物对后代大脑发育的影响
  • 批准号:
    9927684
  • 财政年份:
    2016
  • 资助金额:
    $ 39.91万
  • 项目类别:
An ex-vivo placental perfusion system to study materno-fetal biology
用于研究母胎生物学的离体胎盘灌注系统
  • 批准号:
    7940997
  • 财政年份:
    2009
  • 资助金额:
    $ 39.91万
  • 项目类别:
An ex-vivo placental perfusion system to study materno-fetal biology
用于研究母胎生物学的离体胎盘灌注系统
  • 批准号:
    7843099
  • 财政年份:
    2009
  • 资助金额:
    $ 39.91万
  • 项目类别:

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