There is increasing evidence to suggest that withdrawal of progesterone activity at the level of the uterus is a prerequisite for spontaneous labor in humans, both at term and preterm. Moreover, recent studies have shown that progesterone supplementation can prevent preterm birth in some high-risk women. Although this is the first obstetric intervention that has been shown to effectively delay preterm birth in the past 40 years, its mechanism of action is currently not known.
Progesterone acts in part by binding to progesterone receptors (PR) and modulating the expression of target genes, although non-genomic pathways are also described (Figure 1). We hypothesize that spontaneous preterm labor and birth results from a genetic predisposition to premature withdrawal of progesterone action at the level of the uterus due to differences in PR gene expression and/or function.
To this end, we are investigating:
- The genetics of preterm birth (with particular focus on genetic variations/polymorphisms in progesterone, PR, and PR co-activator/co-repressor genes)
- The effect of progesterone on apoptosis in the fetal membranes (given that one third of preterm birth occurs in the setting of preterm premature rupture of membranes)
- The effect of progesterone supplementation on myometrial contractility both in vivo and in vitro
- The identity of critical cis-DNA elements and cognate trans-factors that mediate tissue-specific expression of the PR gene as well as regulation by progesterone and other hormones
- The functional importance of progesterone-PR signaling in preterm labor
- Identification, characterization, and validation of biomarkers for the prediction of preterm birth (using proteomic / metabolomic analysis of amniotic fluid, cervicovaginal discharge, urine, and serum)
Figure 1: Proposed signaling pathways for progesterone action and the PRs involved
Preeclampsia (gestational proteinuric hypertension) is a major cause of pregnancy-related maternal death. It is estimated that one woman dies every 6 minutes from complications of preeclampsia somewhere in the world. Preeclampsia is also a major cause of perinatal morbidity and mortality, due primarily to the need to deliver the baby in order to save the mother. This is currently the only effective treatment. As such, prompt diagnosis and optimal timing of delivery is critical.
The goal of this research is to better understand the pathogenesis of preeclampsia with a view to improving maternal and perinatal outcome in affected pregnancies. We and others have identified a number of serum and urinary biomarkers for the diagnosis and prediction of preeclampsia, including PP-13, TNFa, and the pro- and anti-angiogenic factors VEGF, PlGF, sFlt1, and sEng.
We have recently identified two novel urinary biomarkers for preeclampsia, namely neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18). We have shown for the first time the presence of NGAL expression at the maternal-fetal interface in vivo (Figure 2) and in purified cytotrophoblast cells in vitro (Figure 3).
To this end, we are investigating:
- The genetics of preeclampsia (with particular focus on genetic variations/polymorphisms in candidate biomarker genes followed by GWAS analysis)
- The utility of NGAL and IL-18 in the prediction and diagnosis of preeclampsia, either singly or in combination with each other or with previously described biomarkers (VEGF, PlGF, sFlt1, and sEng) or uterine artery Doppler velocimetry
- The expression of these putative biomarkers at the maternal-fetal interface in vivo
- The expression and regulation of these putative biomarkers in purified trophoblast cells under basal conditions and conditions of inflammation and hypoxia
Figure 2: IHC showing cytokeratin (A,C) (which labels cytotrophoblasts) and NGAL (B,D) expression in placental tissues with / without intraamniotic infection. Negative control is included as an insert.
Figure 3: Fluorescent ICC showing cytokeratin (A,C) and NGAL (B,D) expression in day 1 (cytotropho-blast) cells in vitro with and without IL-1B treatment. DAPI nuclear staining is shown as insert.
The hypothalamic decapeptide, GnRH (GnRH-I), plays a critical role in regulating mammalian reproductive development and function. In the anterior pituitary, GnRH binds to its target, a heptahelical G-protein coupled receptor known as the GnRH receptor (GnRHR) on the cell surface of pituitary gonadotropes. Here it activates intracellular signal transduction pathways to affect the synthesis and release of the gonadotropins, LH and FSH. These hormones enter the systemic circulation to regulate gonadal function, including steroid hormone synthesis and gametogenesis.
A second isoform of GnRH (GnRH-II) has been identified, and both GnRH-I and -II are produced also by extra-hypothalamic tissues (including ovary, breast, and placenta), where they exert local autocrine/paracrine functions. We hypothesize that GnRH/GnRHR signaling at the maternal-fetal interface may be critically important in regulating events related to implantation, placentation, and the success of human pregnancy.
Specifically, we propose that GnRH may act in an autocrine/paracrine fashion to regulate the production of chemokines, cytokines, and angiogenic factors in trophoblast and/or decidual tissues with important functional implications.