DESCRIPTION (provided by applicant): The objectives of this research and career development proposal are to utilize a nonhuman primate experimental model of intra-amniotic and choriodecidual inoculation with Ureaplasma parvum to characterize the mechanistic and temporal interactions among biomarker expression profiles (i.e., IGFBP-1 proteolytic fragments, calgranulins A and B and annexin II), in maternal and fetal compartments during defined stages of ascending uterine infection. It is our hypothesis that spatial and temporal characteristics of specific biomarkers in cervical vaginal fluid (CVF), amniotic fluid, maternal and fetal blood, will act as surrogates for the stage of progression of intra-uterine infection; similarly, changes in biomarker expression profiles during maternal therapeutic interventions (antibiotic and anti-inflammatory agents), will serve as prognostic indicators. Fetal physiological adaptations to intra-uterine infection will be assessed at intermediate and advanced stages of infection, and in response to maternal therapy. Complementary in vitro studies will determine the tissue sources and production rates of candidate biomarkers, and address the role of matrix metalloproteinases in the proteolytic cleavage of IGFBP-1. Physiological monitoring together with proteomic and molecular studies will address the following questions: (1) Will the immunodetection of specific biomarkers in accessible sampling sites (CVF or maternal blood), correlate with the progression or resolution of intra-uterine infection/inflammation? (2) Will specific biomarker profiles in fetal blood and/or amniotic fluid be linked to microbial localization and fetal hemodynamic responses? (3) Will uterine activity correlate with the choriodecidual or amniotic presence of U. parvum, and with alterations in biomarker profiles in maternal or fetal sampling sites? A number of specific mechanistic endpoints will be ascertained to establish the causal links among progression of Ureaplasma infection and mechanisms of preterm labor. Uterine contractility; amniotic fluid levels of PGE2, PGF2a, cytokines and MMPs will be correlated with the expression of IGFBP-1 proteolytic fragments, calgranulins A and B and annexin II in CVF, amniotic fluid and maternal and fetal blood. Fetal physiologic adaptations to intra-uterine infection will be determined by fetal respiratory parameters (fetal arterial pH, pO2, sO2%), and by Doppler ultrasonography of fetal cardiovascular hemodynamics. Endocrine-immune interactions and the fetal HPA axis will be evaluated by measurements of cortisol, DHEAS, estradiol, progesterone and pro-inflammatory cytokines. The work proposed is unique in its combined use of diagnostic and interventional strategies in a nonhuman primate model of intra-uterine infection (experimental choriodecidual and intra-amniotic stages). It is our expectation that the results of these studies will advance clinical management and facilitate the early diagnosis of women that are at risk for preterm delivery as a consequence of intra-uterine infection.
|Effective start/end date||6/13/08 → 10/31/12|
- National Institutes of Health: $246,510.00
- National Institutes of Health: $237,534.00
- National Institutes of Health: $249,000.00
- National Institutes of Health: $84,205.00