It has recently been concluded that most cases of cerebral palsy (CP) are attributable to perinatal events such as infection and coagulation disorders that activate inflammatory pathways in the fetus and placenta. In this application we propose experiments to elucidate the mechanisms through which microbes trigger inflammatory pathways in the human term placenta. Innate cellular immune responses are mediated by the interaction of pathogens with Toll-like receptors (TLRs). Binding of ligand to TLR activates NF-KB, a transcription factor that stimulates the expression of cytokines and other mediators of inflammation. NF-KB function is suppressed by glucocorticoid (GC) through glucocorticoid receptor (GR) action, although the interaction of TLR and GR pathways in human placenta remains largely unexplored. Our working hypothesis is that GC action modulates TLR-dependent cytokine expression in placental syncytiotrophoblasts (SCTs) and fibroblasts (FIBs) to achieve a dual purpose;protection of the fetus against microbial compounds while limiting inflammation at this site. Furthermore, we postulate that TLR-dependent pathways dominate in pregnancies complicated by fetal/placental inflammation and promote neurological impairment in infants. In our three specific aims we will: 1) determine the mechanism(s) through which GC action suppresses TLR-2,- 3, and -4-mediated cytokine expression in placenta;2) test the hypothesis that SCTs and FIBs, in a TLRdriven process, promote inflammation and recruit monocytes and macrophages to the placental villus in pregnancies associated with chorioamnionitis and neurodevelopmental delay in infants;and 3) test the hypothesis that maternal administration of GC suppresses TLR-4-driven fetal/placental inflammation and neonatal brain injury in mice following intrauterine infusion of LPS on gestational day 15.. For studies we will couple physiologically relevant in vitro techniques of primary cell culture, dual (maternal + fetal) placental perfusion, and mouse knockout models with state of the art molecular methodologies including laser capture microdissection (LCMD) and real-time quantitative PCR (qRTPCR).

Public Health Relevance

Cerebral palsy (CP) can be a devastating disorder that occurs in approximately 2 to 3/1000 live births. It is a major cause of neurological problems in the newborn, and often results in long-term disability. By virtue of our proposed studies, we will determine how bacteria and viruses cause inflammation in the placenta and fetal brain, and how we may stop these processes before they damage the fetus.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD054713-05
Application #
8473083
Study Section
Special Emphasis Panel (ZHD1-MCHG-B)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$238,351
Indirect Cost
$81,245
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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