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.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Primate Research Center Grants (P51)
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Special Emphasis Panel (ZRR1-CM-8 (02))
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University of Washington
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United States
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