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：
Alexandre Bonnin
金额：
$ 39.91万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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

来源：
https://reporter.nih.gov/project-details/10594374
关键词：
Adult Adult Children Behavior Behavioral Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Cell Proliferation Cells Chronic Consensus Data Development Dinoprostone Disease Encephalitis Endothelial Cells Endothelium Etiology Exposure to Extravasation Fetal Development Fetus Functional disorder Gadolinium Genes Genetic Goals Hippocampus Histologic Histology Immune In Vitro Infiltration Inflammation Inflammation Mediators Knock-out Knockout Mice Knowledge Life Light Link Longevity Macrophage Magnetic Resonance Imaging Measures Mediating Methods Microglia Modeling Molecular Mus Myeloid Cells Neurodevelopmental Disorder Outcome PTGS2 gene Pathway interactions Perfusion Pericytes Permeability Phenotype Poly I-C Pregnancy Reporter Research Research Personnel Risk Risk Factors Schizophrenia Structure System Techniques Testing Tight Junctions Time Tracer Vascular Diseases Viral Virus Diseases age related neurodegeneration blood product blood-brain barrier disruption blood-brain barrier function blood-brain barrier permeabilization brain parenchyma celecoxib cerebrovascular conditional knockout cyclooxygenase 2 ex vivo perfusion experience fetal fetal blood glial activation immune activation in utero in vivo knockout gene mimetics molecular pathology mouse model nervous system disorder neuroinflammation neuropathology neurovascular novel offspring postnatal pre-clinical pregnant prenatal prevent response systemic inflammatory response young adult

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.

概括胎儿发育期间母体免疫激活（MIA）增加了神经发育障碍的风险（NDDS）后来的生活。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改变的行为。然而，MIA引起的发展机制持续了尚不清楚整个生命周期的后代大脑小胶质细胞的激活。触发了全身性炎症在成年期间，显示出破坏血脑屏障（BBB）功能，引起小胶质激活，神经炎症并导致神经病理的逐渐出现。即使是可比的在经历妊娠MIA的成年后代中观察到结果，是否有类似的BBB 尚不清楚破坏和导致子宫内这些表型的机制。这是一个重要的知识差距是因为MIA是NND的危险因素，并且越来越多的血管功能障碍的证据促进这些疾病的分子病理。研究人员获得了初步数据，表明孕妇病毒模仿聚（I：c）触发的MIA 小鼠破坏了胎儿BBB的形成，导致使用活胎儿MRI测量的新生BBB渗透率增加。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）途径的激活是MIA效应的因果。重要的是，纵向MRI分析表明胎儿BBB形成的破坏诱导持续的BBB超透明度和终身脑小胶质细胞激活，脑血管炎症，和后代的行为改变。通过四个不同研究小组的联合专业化，研究人员开发了验证了在体内测量胎儿脑BBB通透性的新方法（MRI）和Ex vivo（全胎儿灌注）将使用条件敲除鼠标线来测试：1）if以及如何激活MIA 胎儿小胶质细胞中的Cox2途径在关键时期的胎儿BBB形成，导致不完整的成熟，2）if以及居民中Cox2途径的持久激活如何小胶质细胞延长了后代寿命的BBB结构破坏和神经炎症。这个自我脑部炎症和BBB破坏的永久循环最终会促进增加的风险后代的神经病理学。从病因的角度来看，该临床前建议将定义新的细胞以及参与产前侮辱的终身影响的分子途径，阐明了通过早期炎症与神经发育障碍的血管干扰有因果关系。