Placental Mediated Mechanisms of Perinatal Brain Injury

胎盘介导的围产期脑损伤机制

• 批准号: 9897609
• 负责人: LAUREN Leigh Cooney JANTZIE
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897609
• 关键词: 3-Dimensional; Acute; Adult; Astrocytes; Attenuated; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain region; CXCL1 gene; CXCL2 gene; Cells; Cerebral Palsy; Child; Chronic; Clinical; Cognition; Cognitive; Data; Development; Dose; Environment; Fetus; Flow Cytometry; Functional disorder; Genetic; Hippocampus (Brain); IL8RB gene; Immune; Immunoassay; Immunoblotting; Immunohistochemistry; Impairment; In Vitro; Infant; Infant Mortality; Inflammation; Inflammatory; Injury; Investigation; Knowledge; Learning; Ligands; Link; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; MicroRNAs; Microglia; Modeling; Molecular; Molecular Profiling; Neuraxis; Neurologic; Neuronal Injury; Neurons; Neutrophil Infiltration; Neutrophilic Infiltrate; Oligodendroglia; Pathologic; Perinatal Brain Injury; Pharmacology; Placenta; Pre-Clinical Model; Pregnancy; Problem behavior; Process; Risk Factors; Role; Signal Transduction; Slice; Testing; Transcend; United States; Up-Regulation; attenuation; central nervous system injury; chemokine; critical period; disability; driving force; exosome; fetal; fetal blood; gray matter; high risk; improved; in utero; in vitro Assay; in vivo; intraamniotic infection; knock-down; macrophage; negative affect; nerve injury; nervous system development; neurodevelopment; neutrophil; novel; novel therapeutics; perinatal stroke; postnatal; receptor; recruit; response; spatiotemporal; white matter

Summary In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and long-term disability in children. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. CHORIO contributes to preterm CNS injury, and is also a common, independent risk factor for brain injury in term infants, including perinatal stroke. However, the molecular mechanisms mediating inflammation in the placenta-fetal-brain axis that cause PBI remains a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor (CXCR2) have been clinically implicated in CHORIO, and are essential to neutrophil recruitment, neural cell development and adult CNS injury, although their specific role in PBI pathophysiology is completely undefined. We propose to use our established and unique model of CNS injury associated with CHORIO to delineate how in utero inflammation precipitates PBI. Our central hypothesis is that CXCL1 secreted by the choriodecidua during CHORIO enters fetal blood, transcends the placenta-fetus-fetal brain axis, and through interactions on CXCR2+ neural cells and neutrophil recruitment, confers injury in the developing CNS. We posit that CHORIO is defined by excess CXCL1/CXCR2 signaling, which is toxic to neural cells over an extended neurodevelopmental period. To investigate this hypothesis we will: 1) Test that CHORIO disturbs CXCL1/CXCR2 signaling throughout the placenta-fetus-fetal brain axis during a critical period of late gestation CNS development; 2) Test that placental CXCL1 translocates to the fetal brain and modulates neutrophils and microglia; and 3) Test that attenuation of CXCL1/CXCR2 signal transduction protects neural cells following CHORIO. Using multiplex electrochemiluminescent immunoassay (MECI), flow cytometry (FC), and qPCR we will investigate whether CHORIO induced CXCL1/CXCL2 signaling is a unifying inflammatory signal transduction mechanism through the placenta-fetus-fetal brain axis. Using in vitro assays, including exosome analyses, placental explants and acute brain slices, we will drive CXCL1/CXCR2, and define the major molecular mediators of damage to the placenta-fetus-fetal brain axis. Using immunoneutralization, microRNA, pharmacological (SB225002), and genetic (CXCR2 KO) approaches, we will delineate whether CXCL1/CXCR2 is necessary and sufficient for immune cell recruitment to the CNS following CHORIO. We predict creating a transient CXCR2 deficiency following CHORIO will attenuate microglial activation and neutrophil recruitment, mitigate white matter and neuronal injury, and improve microstructural coherence on magnetic resonance imaging. These investigations will be the first to connect aberrant CXCL1/CXCR2 signaling in the placenta- fetal-brain axis to chronic injury and impaired neurodevelopment, and will define novel targets for directed therapies for infants at high risk for PBI.

概括 在美国，围产期脑损伤（PBI）是婴儿死亡和长期残疾的主要原因 在儿童中。对于大部分患有 PBI 的婴儿来说，中枢神经系统 (CNS) 损伤是在子宫内开始的 炎症（绒毛膜羊膜炎/CHORIO）和/或缺氧缺血。 CHORIO 有助于早产中枢神经系统 损伤，也是足月儿脑损伤（包括围产期中风）的常见独立危险因素。 然而，介导胎盘-胎儿-脑轴炎症导致 PBI 的分子机制 仍然存在知识差距。趋化因子（C-X-C 基序）配体 1 (CXCL1) 及其受体 (CXCR2) 临床上与 CHORIO 有关，对于中性粒细胞募集、神经细胞发育和 成人中枢神经系统损伤，尽管它们在 PBI 病理生理学中的具体作用尚不清楚。我们建议 使用我们建立的、独特的与 CHORIO 相关的中枢神经系统损伤模型来描述子宫内的损伤情况 炎症会引发PBI。我们的中心假设是 CXCL1 在 CHORIO 进入胎儿血液，超越胎盘-胎儿-胎儿脑轴，并通过相互作用 CXCR2+ 神经细胞和中性粒细胞募集，对发育中的中枢神经系统造成损伤。我们假设 CHORIO 是由过量的 CXCL1/CXCR2 信号传导所定义的，该信号传导在长时间内对神经细胞具有毒性。 神经发育期。为了研究这个假设，我们将：1）测试 CHORIO 是否会干扰 妊娠晚期关键时期CXCL1/CXCR2信号传导贯穿胎盘-胎儿-胎儿脑轴 中枢神经系统发育； 2) 测试胎盘CXCL1易位至胎儿大脑并调节中性粒细胞和 小胶质细胞； 3) 测试 CXCL1/CXCR2 信号转导的减弱可以保护神经细胞 乔里奥。我们使用多重电化学发光免疫分析 (MECI)、流式细胞术 (FC) 和 qPCR 将研究 CHORIO 诱导的 CXCL1/CXCL2 信号传导是否是统一的炎症信号 通过胎盘-胎儿-胎儿脑轴的转导机制。使用体外测定，包括外泌体 分析、胎盘外植体和急性脑切片，我们将驱动 CXCL1/CXCR2，并定义主要 胎盘-胎儿-胎儿脑轴损伤的分子介质。使用免疫中和、microRNA、 药理学（SB225002）和遗传（CXCR2 KO）方法，我们将描述CXCL1/CXCR2是否 对于 CHORIO 后免疫细胞募集到 CNS 来说是必要且充分的。我们预测创建一个 CHORIO 后短暂的 CXCR2 缺乏会减弱小胶质细胞的激活和中性粒细胞的募集， 减轻白质和神经元损伤，并改善磁共振的微观结构一致性 成像。这些研究将首次将胎盘中异常的 CXCL1/CXCR2 信号联系起来。 胎儿脑轴慢性损伤和神经发育受损，并将确定定向的新靶点 针对 PBI 高危婴儿的治疗。