EXPERIMENTAL MODEL FOR CHORIOAMNIONITIS AND PRETERM LABOR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的总体目标是阐明感染诱发早产的机制，以制定合理的干预策略来预防早产和早产的新生儿后遗症(即脑损伤)。羊膜内感染是早产的主要原因。对细菌的免疫反应被认为是导致感染导致早产的原因，目前还没有有效的预防早产的疗法。如果预防早产和胎儿损伤的干预措施要成为现实的目标，那么需要在模拟人类疾病的模型中阐明在宫颈、子宫、胎盘和胎儿中激活的反应感染和炎症的途径。我们建议建立一个早产模型，通过模仿恒河猴上升的下生殖道感染，比以前的动物模型更接近地复制人类早产的自然历史。初步数据表明，绒毛-蜕膜接种GBS会导致一系列事件，从细菌穿过胎盘膜进入羊水开始，伴随着细胞因子和前列腺素的增加，随后是早产。新模型将在怀孕母体子宫下段的绒毛-蜕膜界面引入GBS，监测感染前和感染期间的母婴生理反应，并顺序采样母体、胎儿和羊水室。我们还计划通过基因组和蛋白质组技术，在收集的液体和组织样本中调查母体和胎儿的炎症反应。我们相信这些初步实验将为我们的长期目标奠定基础，这些目标包括：1)阐明上升感染诱导早产的病理生理机制；2)利用基因组学建立宫内感染和早产之间的细胞和分子联系；以及3)开发检测感染相关早产的非侵入性诊断策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective of this project is to elucidate mechanisms of infection-induced preterm labor in order to develop rational interventional strategies to prevent preterm birth and neonatal sequelae of prematurity (i.e. brain injury). Intra-amniotic infection causes the majority of early preterm births. Immune responses to bacteria are thought to drive infection-induced preterm labor and no effective therapy to prevent preterm birth currently exists. If interventions to prevent preterm birth and fetal injury are to become realistic goals, then the pathways that are activated in the cervix, uterus, placenta and fetus in response to infection and inflammation need to be elucidated in a model which emulates human disease. We propose to establish a model of preterm labor that more closely replicates the natural history of human preterm labor than prior animal models, by mimicking an ascending lower genital tract infection in a rhesus monkey. Preliminary data suggests that chorio-decidual inoculation of GBS results in a sequential pattern of events beginning with translocation of bacteria across the placental membrane into the amniotic fluid, with associated increases in cytokines and prostaglandins, followed by preterm labor. The new model will introduce GBS at the chorio-decidual interface in the lower uterine segment of a pregnant dam, monitor maternal and fetal physiological responses before and during infection, and sequentially sample the maternal, fetal, and amniotic fluid compartments. We also plan to investigate the maternal and fetal inflammatory responses in the collected fluid and tissue samples, by genomic and proteomic technology. We believe these initial experiments will lay the foundation for our longer term objectives which include: 1) to elucidate the pathophysiologic mechanisms of ascending infection-induced preterm labor; 2) to establish the cellular and molecular links among intrauterine infection and preterm labor using genomics; and 3) to develop non-invasive diagnostic strategies for detecting infection-associated preterm labor.