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）是婴儿死亡率和长期残疾的主要原因 在儿童中。对于大部分PBI婴儿，中枢神经系统（CNS）损伤在子宫内开始 炎症（绒毛膜炎/绒毛膜炎）和/或缺氧 - 缺血。合唱有助于早产中心 损伤，也是脑损伤（包括围产期中风）的常见独立危险因素。 然而，介导胎盘 - 脑脑轴中炎症的分子机制，引起PBI 仍然是知识的差距。趋化因子（C-X-C基序）配体1（CXCL1）及其受体（CXCR2）具有 在临床上与合唱有关，对于中性粒细胞募集，神经细胞的发育和 成人中枢神经系统损伤，尽管它们在PBI病理生理学中的特定作用是完全不确定的。我们建议 使用我们与Chorio相关的CNS损伤的既定模型来描述子宫 炎症会沉淀PBI。我们的中心假设是，CXCL1在 合唱者进入胎儿血液，超越胎盘 - 狂热脑轴，并通过上的相互作用 CXCR2+神经细胞和中性粒细胞募集，赋予了发育中的CNS的损伤。我们认为那个合唱 由过量的CXCL1/CXCR2信号定义，该信号传导对神经细胞有毒 神经发育期。为了调查这一假设，我们将：1）测试唱片干扰 CXCL1/CXCR2信号传导整个胎盘 - 爆发脑轴均在妊娠的关键时期 中枢神经系统开发； 2）测试胎盘CXCL1易位到胎儿大脑并调节中性粒细胞和 小胶质细胞； 3）测试CXCL1/CXCR2信号转导的衰减，可保护神经细胞 合唱团。使用多重电化学发光免疫测定（MECI），流式细胞仪（FC）和QPCR WE 将研究Chorio诱导的CXCL1/CXCL2信号是否是统一的炎症信号 通过胎盘 - 爆发脑轴轴的转导机制。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 对胎盘 - 开发脑脑轴损伤的分子介质。使用免疫中和化microRNA， 药理学（SB225002）和遗传（CXCR2 KO）方法，我们将描述CXCL1/CXCR2是否 在合唱之后，必要且足够用于对中枢神经系统的免疫细胞募集。我们预测创建一个 Chorio后的瞬时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，并提高磁共振上的微结构连贯性 成像。这些研究将是第一个连接胎盘中异常CXCL1/CXCR2信号传导的研究。 胎儿脑轴慢性损伤和神经发育受损，并将定义针对的新目标 PBI高风险的婴儿的疗法。