Premature rupture of the fetal membranes is a major cause of maternal morbidity and premature birth. Studies performed during the past funding period implicate increased expression of matrix metalloproteinases (MMP), particularly collegenases and gelatinases in the normal as well as the preterm rupture of the fetal membranes (PROM). We now propose to test hypotheses regarding mechanisms that induce and amplify expression of MMPs in the fetal membranes; and the role of genetic variation in MMP genes in increasing the risk of preterm premature rupture (PPROM). We will determine whether proteolytic fragments of fibronectin induce MMP expression in human amnion cells in vitro; define the receptor(s) and signal transduction cascade underlying this response; identify active fibronectin proteolytic fragments in cervico-vaginal secretions and amniotic fluid and correlate their presence with preterm birth. Our primary hypothesis is that fetal fibronectin is more than a marker of impending parturition and that proteolytic fragments of this protein act as signaling molecules in the fetal membranes, inducing expression of MMPs and thus promoting the degradation of the fetal membrane extracellular matrix. We will explore the association of genetic variation in the MMP-1 (collagenase) and MMP-9 (gelatinase) genes with increased risk of PPROM. We will determine whether specific polymorphisms augment MMP promoter activity and gene expression in human amnion cells. The hypothesis to be tested is that genetic variation in MMP gene promoter regions influences the level of MMP expression. We will then determine in a case-control study whether alleles linked to increased MMP expression are more prevalent in PPROM. The hypothesis to be tested is that genetic factors governing extracellular matrix metabolism in the fetal membranes are linked to risk of PPROM. The proposed studies have the potential to reveal novel biochemical and genetic risk factors for PPROM and preterm birth, and to identify molecular mechanisms of PPROM that could be exploited for therapeutic intervention.
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