The Role of Choriodecidual Infection in the Pathogenesis of Preterm Birth and Inflammatory Brain Injury

摘要 这项建议的目的是评估早期上升生殖道感染的作用。 (即绒毛蜕膜感染)在启动母婴炎症反应中的作用 胎儿脑部炎症和损伤的机制。中心假设是母体-胎儿 绒毛蜕膜感染微小解脲支原体后的炎症反应启动了早期的 早产，在微生物侵入羊膜腔之前，会导致“不孕症”的出现 胎儿发炎和脑损伤。实验范式[利用了一名长期留置尿管的孕妇 绒毛蜕膜接种恒河猴模型]105dGA(孕期~168日龄)感染微小解脲支原体。我们 预测这一新的方法将模拟宫内解脲支原体感染上升的自然过程 人类怀孕，提供了感染驱动的胎儿炎症模型，没有直接的微生物暴露 胎儿。这将使我们能够评估[胎儿炎症反应的启动]。CO-2的初步数据 小胶质细胞增多症患者透明质酸的定位提示围产期炎症的新机制 脑损伤是通过中介作用的。[将评估早产综合征的各个方面，以确定如何 导致宫颈成熟、胎膜变弱和子宫收缩的炎性介质 也可能会影响发育中的大脑。]组织学评估将确定蜕膜炎的程度， 绒毛膜羊膜炎，膜结构和完整性。[腹部超声和Bishop评分将是 分别用于确定宫颈缩短和扩张。]持续的生理监测 将通过留置导尿管进行子宫压力和羊水和母体血液的连续采样 在手术中植入。将测量促炎介质(细胞因子、前列腺素、MMPs)的表达 在这些样本中，以及在脐带血、胎儿脑脊液和胎儿脑组织和肺组织中。分娩时，胎儿的大脑将 检查大体病理变化以及炎症和损伤的组织学证据。特定标记 对于少突胶质细胞的成熟和小胶质细胞的激活将被识别并与MRI表现和 透明质酸蓄积的位置。透明质酸受体和代谢物的表达也将 用免疫组织化学方法测定。该提议的主要优点在于独特的非人类灵长类动物 基于初步数据的解脲支原体绒毛蜕膜感染模型此应用程序和关联的 职业发展计划将为候选人在未来继续进行独立研究奠定基础 围产期和生殖生物学领域。[生物统计学、研究设计、实验室的正式课程 管理/领导力与神经科学技术的具体培训相结合，非人类灵长类 OHSU大脑与行为发展研究小组的研究技能和成员 发育健康中心和神经退化杂志俱乐部正式确定培训机会， 科学交流和职业发展]。

Summary The objectives of this proposal are to assess the role of the early stages of ascending reproductive tract infection (i.e. choriodecidual infection) in the initiation of maternal and fetal inflammatory responses that activate mechanisms of inflammation and injury in the fetal brain. The central hypothesis is that maternal-fetal inflammatory responses following choriodecidual infection with U. parvum initiate early processes of preterm labor, prior to microbial invasion of the amniotic cavity, leading to the appearance of “sterile” fetal inflammation and brain injury. The experimental paradigm [utilizes a chronically catheterized pregnant rhesus monkey model of choriodecidual inoculation] with Ureaplasma parvum at 105dGA (term~168 days). We predict this novel approach will mimic the natural course of ascending intra-uterine Ureaplasma infection during human pregnancy, providing a model of infection-driven fetal inflammation, without direct microbial exposure of the fetus. This will allow us to assess the [initiation of fetal inflammatory responses.] Preliminary data of co- localization of hyaluronic acid with microgliosis suggests a novel mechanism by which perinatal inflammatory brain injury is mediated. [Aspects of the preterm labor syndrome will be assessed to determine how inflammatory mediators that lead to cervical ripening fetal membrane weakening and uterine contractility may also affect the developing brain.] Histological assessments will determine the extent of deciduitis, chorioamnionitis, and membrane structure and integrity. [Abdominal ultrasound and Bishop score will be employed to determine cervical shortening and dilation, respectively.] Continuous physiological monitoring of uterine pressure and serial sampling of amniotic fluid and maternal blood will occur via indwelling catheters implanted at surgery. Pro-inflammatory mediator expression (cytokines, prostaglandins, MMPs) will be measured in these samples, as well as in cord blood, fetal CSF and fetal brain and lung tissue. At delivery, fetal brains will be examined for gross pathological changes and histologic evidence of inflammation and injury. Specific markers for oligodendrocyte maturation and microglial activation will be identified and correlated to MRI findings and location of hyaluronic acid accumulation. Hyaluronic acid receptor and metabolite expression will also be determined by immunohistochemistry. Major strengths of the proposal lie in the unique non-human primate model of Ureaplasma choriodecidual infection based on preliminary data. This application and the associated career development plan will provide a foundation for the Candidate’s continued independent research in the fields of perinatal and reproductive biology. [Formal tuition in biostatistics, research design, lab management/leadership coupled with specific training in neuroscience techniques, non-human primate research skills and membership of the Brain & Behavioral Development research group part of the OHSU Center for Developmental Health and the Neurodegeration Journal Club formalize opportunities for training, scientific exchange and career development].