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.
总结 胎儿发育期间母体免疫激活(MIA)增加神经发育障碍的风险 在后代的生活中,妊娠期MIA暴露的成年后代中的慢性小胶质细胞活化 导致一系列行为改变然而,MIA诱导这种持续的发展机制 后代脑小胶质细胞在整个生命周期中的激活尚不清楚。全身性炎症触发 在成年期间,显示破坏血脑屏障(BBB)功能,诱导小胶质细胞活化, 神经炎症并导致神经病理学的逐渐出现。虽然可比 在经历妊娠MIA的成年后代中观察结果,是否存在类似的BBB 破坏和导致子宫内这些表型的机制尚不清楚。这是一个重要 由于MIA是NND的风险因素,并且有越来越多的证据表明血管功能障碍,因此存在知识差距 导致这些疾病的分子病理学。 研究人员获得的初步数据显示,MIA由病毒模拟物poly(I:C)在妊娠中触发。 小鼠破坏胎儿BBB形成,导致使用活胎儿MRI测量的新生BBB渗透性增加。 他们的数据进一步表明,在胎儿脑小胶质细胞中,环氧化酶-2(COX 2; Ptgs 2)通路的激活 是MIA效应的原因重要的是,纵向MRI分析表明,胎儿血脑屏障形成的破坏 诱导持续的BBB高通透性和终生的脑小胶质细胞活化,脑血管炎症, 以及后代的行为改变 通过四个不同研究小组的综合专业知识,研究人员开发并 经验证的用于测量体内(MRI)和离体(全胎儿)胎儿脑BBB渗透性的新方法 灌注),其与条件性敲除小鼠系一起将用于测试:1)MIA激活是否以及如何激活 胎儿小胶质细胞中COX 2途径的激活会在发育的关键时刻扰乱胎儿BBB的形成,导致 不完全成熟,和2)如果和如何导致长期激活COX 2途径在居民 小胶质细胞在后代的生命周期中导致BBB结构破坏和神经炎症。这个自我- 脑炎症和BBB破坏的永久循环最终会增加患上脑血管疾病的风险。 后代的神经病理学。从病因学的角度来看,这一临床前建议将定义新的细胞 和参与产前损伤终身影响的分子途径,揭示了 其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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