TOLL-LIKE RECEPTOR ANATAGONISM AS TREATMENT FOR PRETERM LABOR

Toll 样受体拮抗作用作为早产的治疗

• 批准号: 8172768
• 负责人: KRISTINA M. ADAMS WALDORF
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172768
• 关键词: Amniotic Fluid; Bacteria; Brain Injuries; Cervix Uteri; Computer Retrieval of Information on Scientific Projects Database; Escherichia coli; Fetal Membranes; Fetus; Funding; Goals; Grant; Immune response; Infection; Inflammation; Inflammatory Response; Injury; Institution; Intervention; Lipopolysaccharides; Mediator of activation protein; Modeling; Neonatal; Pathogenesis; Pathway interactions; Placenta; Premature Birth; Premature Labor; Research; Research Personnel; Resources; Signal Transduction; Source; Toll-like receptors; United States National Institutes of Health; Variant; effective therapy; fetal; human disease; intraamniotic infection; mutant; nonhuman primate; premature; prevent; response; toll-like receptor 4; trafficking

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. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该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会导致感染引起的早产，目前尚无有效的疗法来预防早产。 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子宫颈、子宫、胎盘和胎儿响应感染和炎症而激活的途径。 拟议的研究将使用大肠杆菌和脂多糖（LPS）在长期插入导管的非人灵长类动物（NHP）中建立一种新的早产模型，以诱导羊膜内感染。 我们的主要假设是，Toll 样受体 4 (TLR4) 信号传导引起的炎症通过启动炎症反应，是早产发病机制中的关键介质。 TLR4 识别 LPS（一种革兰氏阴性细菌产物）。 通过使用具有 LPS 结构变异的细菌突变体来剖析母体炎症反应，可以建立 TLR4 信号传导的层次结构，这可能有助于细菌穿过胎膜进入羊水。