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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000166-50
Application #
8357604
Study Section
Special Emphasis Panel (ZRR1-CM-8 (02))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$156,634
Indirect Cost
Name
University of Washington
Department
Veterinary Sciences
Type
Other Domestic Higher Education
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
McAdams, Ryan M; McPherson, Ronald J; Kapur, Raj P et al. (2017) Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates. Dev Neurosci 39:107-123
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Rembado, Irene; Zanos, Stavros; Fetz, Eberhard E (2017) Cycle-Triggered Cortical Stimulation during Slow Wave Sleep Facilitates Learning a BMI Task: A Case Report in a Non-Human Primate. Front Behav Neurosci 11:59
Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola et al. (2016) Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic. Mol Ther Methods Clin Dev 5:16013
McLoon, Linda K; Christiansen, Stephen P; Ghose, Geoffrey M et al. (2016) Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment. Invest Ophthalmol Vis Sci 57:6070-6078
Liao, Hsi-Wen; Ren, Xiaozhi; Peterson, Beth B et al. (2016) Melanopsin-expressing ganglion cells on macaque and human retinas form two morphologically distinct populations. J Comp Neurol 524:2845-72

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