TOLL-LIKE RECEPTOR ANATAGONISM AS TREATMENT FOR PRETERM LABOR

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本项目的总体目标是阐明感染引起早产的机制，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）。 羊膜内感染导致大多数早期早产。 对细菌的免疫反应被认为是感染诱导的早产，目前还没有有效的治疗方法来预防早产。 如果预防早产和胎儿损伤的干预措施成为现实的目标，那么在宫颈，子宫，胎盘和胎儿中激活的响应感染和炎症的途径需要在模拟人类疾病的模型中阐明。 本研究拟建立一种新的非人灵长类早产动物模型。大肠杆菌和脂多糖（LPS）诱导羊膜内感染。 我们的主要假设是由Toll样受体4（TLR 4）信号传导引起的炎症是早产发病机制中的关键介质，通过启动炎症反应。 TLR 4识别LPS，一种革兰氏阴性细菌产物。 通过使用具有LPS结构变体的细菌突变体来剖析母体炎症反应，可以建立TLR 4信号传导的层次结构，所述母体炎症反应可以帮助细菌穿过胎膜运输到羊水中。 我们独特的长期插管的非人灵长类动物模型提供了一个独特的和强大的手段来研究TLR信号在绒毛膜蜕膜膜界面，细菌触发一些情况下的早产被认为是穿越。 进一步发展我们独特的灵长类动物模型可以为探索感染诱导早产的机制和研究预防早产的新干预策略提供重要手段。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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. The proposed study will establish a new model of preterm birth in a chronically catheterized nonhuman primate (NHP) using E. coli and lipopolysaccharide (LPS) to induce an intra-amniotic infection. Our main hypothesis is that inflammation resulting from toll-like receptor 4 (TLR4) signaling is a critical mediator in the pathogenesis of preterm labor, by initiating an inflammatory response. TLR4 recognizes LPS, a gram-negative bacterial product. A hierarchy of TLR4 signaling can be established by using bacterial mutants with LPS structural variants to dissect maternal inflammatory responses that may aid bacteria in trafficking across the fetal membranes into the amniotic fluid. Our unique chronically catheterized nonhuman primate model provides a unique and powerful means to study TLR signaling at the choriodecidua-membrane interface across which bacteria triggering some cases of preterm labor are thought to traverse. Further development of our unique primate model could provide an important means for exploring the mechanisms involved in infection induced preterm labor and investigating new interventional strategies to prevent premature birth.