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

总结 本提案的目的是评估上行生殖道感染早期阶段的作用 (i.e.绒毛膜蜕膜感染）在母体和胎儿炎症反应的启动中， 胎儿脑内炎症和损伤的机制。核心假设是母胎 绒毛膜蜕膜感染U.微小体启动早期过程 早产，在微生物侵入羊膜腔之前，导致“无菌”的外观 胎儿炎症和脑损伤实验范例[利用一个长期插管的孕妇 恒河猴绒毛膜蜕膜接种模型]在105 dGA（足月~168天）时接种微小脲原体。我们 预测这种新的方法将模拟子宫内支原体感染上升的自然过程， 人类妊娠，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。初步数据共- 透明质酸与小胶质细胞增生的定位提示了围产期炎症反应的一种新机制， 脑损伤是介导的。[早产综合征的各个方面将进行评估，以确定如何 导致宫颈成熟、胎膜弱化和子宫收缩力的炎症介质 也可能影响大脑发育。组织学评估将确定蜕膜炎的程度， 绒毛膜炎和膜结构和完整性。[腹部超声和Bishop评分将 用于分别确定宫颈缩短和扩张。连续生理监测 将通过留置导管进行子宫压力和羊水和母体血液的连续采样 手术时植入。将测量促炎介质表达（细胞因子、胰高血糖素、MMP） 在这些样品中，以及在脐带血、胎儿CSF和胎儿脑和肺组织中。分娩时，胎儿的大脑 检查大体病理变化和炎症和损伤的组织学证据。特异性标志物 将识别少突胶质细胞成熟和小胶质细胞活化，并与MRI结果相关， 透明质酸积累的位置。透明质酸受体和代谢物的表达也将被 通过免疫组织化学测定。该提案的主要优势在于独特的非人类灵长类动物 根据初步数据建立的绒毛膜蜕膜脲原体感染模型。此应用程序和相关的 职业发展计划将为候选人继续独立研究提供基础， 围产期和生殖生物学领域。[生物统计学，研究设计，实验室的正式学费 管理/领导力加上神经科学技术的具体培训，非人灵长类动物 研究技能和OHSU大脑与行为发展研究小组成员 发展健康中心和神经退化杂志俱乐部正式提供培训机会， 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].