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: 7958876
• 负责人: KRISTINA M. ADAMS WALDORF
• 金额: $ 31.52万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958876
• 关键词: Amniotic Fluid; Bacteria; Brain Injuries; Cervix Uteri; Computer Retrieval of Information on Scientific Projects Database; Development; Escherichia coli; Fetal Membranes; Fetus; Funding; Goals; Grant; Immune response; Infection; Inflammation; Inflammatory Response; Injury; Institution; Intervention; Lipopolysaccharides; Mediator of activation protein; Membrane; Modeling; Neonatal; Pathogenesis; Pathway interactions; Placenta; Premature Birth; Premature Labor; Primates; 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. 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的总体目的是阐明感染引起的早产劳动的机制，以制定理性的介入策略，以防止早产和过早的新生儿后遗症（即脑损伤）。 - 肿瘤内感染会导致大多数早产。 人们认为对细菌的免疫反应促进了感染引起的早产劳动，并且没有有效的疗法来防止早产。 如果要预防早产和胎儿损伤的干预措施成为现实的目标，则需要在模仿人类疾病的模型中阐明子宫颈，子宫，胎盘和胎儿在子宫颈，子宫，胎盘和胎儿中被激活的途径。 拟议的研究将使用大肠杆菌和脂多糖（LPS）在长期导管的非人类灵长类动物（NHP）中建立一种新的早产模型，以诱导肿瘤内感染。 我们的主要假设是，通过炎症反应引发炎症反应，是由Toll样受体4（TLR4）信号引起的炎症是早产的重要介体。 TLR4识别LPS，一种革兰氏阴性细菌产物。 可以通过使用具有LPS结构变体的细菌突变体来解剖孕产妇炎症反应，从而建立TLR4信号传导的层次结构，这些突变体可能有助于细菌在胎儿膜中运输到羊水中。 我们独特的慢性导管非人类灵长类动物模型提供了一种独特而有力的方法，可以在脉络膜上研究TLR信号传导，触发某些早产劳动的细菌被认为是横穿的。 我们独特的灵长类动物模型的进一步发展可以为探索感染引起的早产劳动的机制提供一种重要手段，并调查了防止过早出生的新介入策略。