Preterm delivery, which complicates 8-10% of pregnancies in the United States, results in significant neonatal and pediatric morbidity, and is responsible for about 75% of the neonatal mortality. The mechanisms underlying the onset of preterm labor are unclear; however, studies to date suggest that preterm delivery is often associated with genital tract infection, as suggested by elevated proinflammatory cytokines (e.g. IL2, ILa, TNF-a, and IFN-g). Although it has been shown that these cytokines lead to increased prostaglandin production by intrauterine tissues, it is unclear whether this is the only mechanism by which these pro-inflammatory cytokines lead to the stimulation of preterm contractions. The research described in this RO1 application will test the hypothesis: endotoxin (LPS) stimulates increased proinflammatory cytokines, especially IL-2, TNF-a and IFN-g resulting in activation of the """"""""thrombin stimulated intrauterine signaling pathway""""""""; i.e. enhanced phospholipid scramblase (PLS), tissue prothrombinase (Fgl2), prothrombin and thrombin receptor (PAR1) expression and activation leading to preterm contractions and delivery. Our preliminary studies have confirmed the molecular expression of all of the components of this pathway within the near term rat uterus. Using the LPS-induced preterm delivery model in the timed-pregnant rat, we will complete the following specific aims: 1) determine if Fgl2 expression and activation are increased in the preterm rat uterus, leading to prothrombinase activity, 2) determine if phospholipid scramblase expression and functional activity increase in the preterm rat uterus, leading to enhanced Fgl2 activity, 3) determine if increased intrauterine prothrombin expression occurs, leading to enhanced thrombin generation, 4) determine if uterine PAR-1 expression and activation are increased, leading to myometrial contractions, decidual necrosis, and intrauterine bleeding, and 5) test the hypothesis that the above phenomena occur in parallel and contribute to the role of prostaglandins during the events leading to LPS-stimulated preterm labor and delivery in the rat. These studies are anticipated to significantly improve our understanding of the mechanisms underlying preterm labor in the presence of intrauterine infection.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044747-05
Application #
7228973
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
2003-07-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$258,570
Indirect Cost
Name
University of Vermont & St Agric College
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
McLean, Kelley C; Oppenheimer, Karen H; Sweet, Leigh M et al. (2012) Phospholipid scramblase expression in the pregnant mouse uterus in LPS-induced preterm delivery. Reprod Sci 19:1211-8
Phillippe, Mark; Diamond, Allaire K; Sweet, Leigh M et al. (2011) Expression of coagulation-related protein genes during LPS-induced preterm delivery in the pregnant mouse. Reprod Sci 18:1071-9
Phillippe, Mark; Sweet, Leigh M; Bradley, Diana F et al. (2009) Role of nonreceptor protein tyrosine kinases during phospholipase C-gamma 1-related uterine contractions in the rat. Reprod Sci 16:265-73
Bizargity, Peyman; Del Rio, Roxana; Phillippe, Mark et al. (2009) Resistance to lipopolysaccharide-induced preterm delivery mediated by regulatory T cell function in mice. Biol Reprod 80:874-81
Diamond, Allaire K; Sweet, Leigh M; Oppenheimer, Karen H et al. (2007) Modulation of monocyte chemotactic protein-1 expression during lipopolysaccharide-induced preterm delivery in the pregnant mouse. Reprod Sci 14:548-59
Phillippe, Mark; Sweet, Leigh M; Engle, Daniel (2007) The role of phospholipase Cgamma1 tyrosine phosphorylation during phasic myometrial contractions. Am J Obstet Gynecol 196:179.e1-7
Phillippe, Mark; Bradley, Diana F; Phillippe, Kathrynn et al. (2006) Tissue prothrombinase activity in myometrium from timed-pregnant rats. J Soc Gynecol Investig 13:477-82
Phillippe, Mark; Bradley, Diana F; Ji, Huiling et al. (2006) Phospholipid scramblase isoform expression in pregnant rat uterus. J Soc Gynecol Investig 13:497-501
Phillippe, Mark; Bradley, Diana F; Engle, Daniel et al. (2006) SHP protein tyrosine phosphatase expression in rat uterine tissue. J Soc Gynecol Investig 13:338-42