The objectives of this research proposal are to characterize the mechanistic and temporal relationships among biomarker expression profiles (e.g., IGFBP-1 proteolytic fragments, calgranulin B and annexin II) in maternal and fetal compartments during defined stages of ascending infection with genital mycoplasmas (from choriodecidual to intra-amniotic models). It is our hypothesis that spatial and temporal characteristics of specific proteomic 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 (i.e., cardiovascular hemodynamics, respiratory parameters,endocrine status) will be assessed in early and advanced stages of infection, and in response to maternal antibiotic therapy. Complemetary in vitro studies will assess the ability of U. parvum to invade and transcytose through intact chorioamniotic membranes and gain entry into the amniotic cavity. The production rates of specific biomarkers and the secretory profiles of IL-1B, TNF-a, IL-6 and IL-8 by component tissue layers will illuminate the tissue source of specific biomarker profiles observed in the amniotic fluid and cervical vaginal fluid (CVF) during intra-uterine infection. Moreover, these studies will provide important information on the contribution of the amnion or choriodecidua to the inflammatory response following U. parvum exposure. A number of specific endpoints will be ascertained that will aid in our understanding of causal links among choriodecidual colonization with U. parvum and the biologic and clinical manifestations of early and late stages of ascending uterine infection. Uterine contractility, serial assesment of cervical length (by ultrasound and palpation), amniotic fluid levels of PGE2, PGF2a, cytokines, leukocytes and MMPs will be correlated with biomarker expression profiles in the CVF, amniotic fluid and maternal and fetal blood. Quantitative cultures and PCR for ureaplasmas will be performed on amniotic fluid, blood and fetal tissues.
Ascending uterine infection by genital mycoplasmas is a predominant cause of early preterm birth, yet the the stages of disease progression (from bacterial vaginosis to intra-amniotic infection), are incompletely understood. This proposal will expand our understanding of the pathophysiology of preterm labor and develop new approaches to prevent prematurity (diagnosis to therapeutic strategies) and neonatal sequelae.
| Kelleher, Meredith A; Liu, Zheng; Wang, Xiaojie et al. (2017) Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection. Pediatr Res 82:244-252 |
| Acosta, Edward P; Grigsby, Peta L; Larson, Kajal B et al. (2014) Transplacental transfer of Azithromycin and its use for eradicating intra-amniotic ureaplasma infection in a primate model. J Infect Dis 209:898-904 |
| Grigsby, Peta L; Novy, Miles J; Sadowsky, Drew W et al. (2012) Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. Am J Obstet Gynecol 207:475.e1-475.e14 |
| Roberts, V H J; Räsänen, J P; Novy, M J et al. (2012) Restriction of placental vasculature in a non-human primate: a unique model to study placental plasticity. Placenta 33:73-6 |
