There is a key gap in knowledge with respect to mechanisms leading to preterm premature rupture of fetal membranes (PPROM). Continued existence of this gap represents an important problem because, until it is filled, the development of successful strategies for the prevention and treatment of PPROM will remain elusive. The long-term goal of this proposal is to reduce the incidence of PPROM-induced preterm birth. The objective here is to determine the extracellular matrix mechanisms that lead to PPROM. The central hypothesis for this proposal is that the extracellular matrix proteoglycans biglycan and decorin contribute to the maintenance of intact fetal membranes throughout gestation. This hypothesis is based on preliminary data that support a role for these mechanisms in maintenance of pregnancy. Preliminary studies show that the absence of biglycan and decorin in mice leads to preterm birth, abnormal fetal membrane morphology and altered signaling pathways, and that the phenotype is enhanced on exposure to inflammation. Furthermore, human fetal membranes with PPROM display decorin dysregulation. The rationale for the proposed research is that completion of these aims will define key biglycan- and decorin-dependent mechanisms that contribute to the integrity of fetal membranes, resulting in new and innovative strategies for the prevention and treatment of PPROM. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify the contributions of the proteoglycans biglycan and decorin to successful gestation using mice deficient in these proteoglycans; 2) Identify the mechanisms by which the extracellular matrix contributes to the structural integrity of the fetal membranes throughout gestation in the biglycan/decorin knockout mouse; and 3) Elucidate the status of the extracellular matrix in fetal membranes after PPROM in humans. Under the first aim, a maternal-fetal divergent genotype approach will be used to assess the extracellular matrix contribution to fetal membrane stability. For the second aim, fetal membrane biomechanical testing and recombinant biglycan rescue testing will be performed. For the third aim, human fetal membrane proteoglycan expression will be assessed. Each approach has been established as feasible in the applicants' hands. The contribution of the proposed research is expected to be the identification of novel biglycan- and decorin- dependent mechanisms that contribute to protection against PPROM. The proposed research is innovative because it represents a new and substantive departure from the status quo, namely the approach of extracellular matrix proteoglycan contribution to the stability of the fetal membranes using knockout fetal membrane mechanical testing, proteoglycan therapy and embryo transfer. The proposed research is significant because it is expected to vertically advance our understanding of extracellular matrix contribution to the stabilization of the fetal membranes throughout pregnancy. Ultimately, such knowledge has the potential to inform the development of new preventive and therapeutic strategies for PPROM.
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