JEFF REESE, MD
department of pediatrics
Our lab is interested in the mechanisms of embryo-uterine interactions at the time of implantation and fetal-maternal interactions at the time of birth. During early pregnancy, a tightly regulated series of molecular signals coordinates uterine receptivity and activation of the developing embryo. In collaboration with other Vanderbilt investigators, we are examining the role of growth factors, cytokines and prostaglandins in the establishment of pregnancy. Genomic screens have also identified numerous factors that are upregulated at the time of implantation, but whose function in this process is unknown. Current research projects are aimed at resolving the contribution of these gene families to embryo implantation.
We are also examining the role of prostaglandins in term and preterm birth. Prostaglandins are products of arachidonic acid metabolism with vasoactive and mitogenic properties, and are likely downstream mediators of growth factor signaling. Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandin synthesis. COX-1 is the constitutive isoform of this enzyme whose expression is developmentally regulated, while COX-2 is expressed in response to inflammatory stimuli. We observed reduced vascular permeability and prostaglandin concentrations in the uteri of COX-1 deficient mice. However, COX-1 deficient uteri have compensatory upregulation of COX-2, suggesting a mechanism to preserve fertility. COX-1 null mice are also remarkable for their inability to complete labor or deliver healthy pups. We found that COX-1 deficient mice can deliver in a timely fashion when carrying a litter of wildtype pups (by embryo transfer). There are few mouse models that display parturition failure and offer the opportunity to examine the molecular basis of labor. As part of these studies, COX-1/COX-2 double knockout mice have also been bred. These mice have perinatal lethality, possibly due to abnormal regulation of the ductus arteriosus, a fetal vascular shunt that is necessary for survival in-utero. These models are invaluable resources for the evaluation of prostaglandin actions in maternal-fetal communication during reproduction and during fetal organogenesis.