During the final trimester of pregnancy the uterus undergoes a remarkable transition from a state of relative quiescence to that of an active contractile unit. The priming of the pregnant uterus for contraction is associated with increased oxytocin receptors, increased gap junctions and cervical ripening. In most mammalian species but not the human a precipitous decline in circulating levels of progesterone (P4) also heralds the onset of labor. There is a growing body of evidence that inhibition of uterine progesterone receptor (PR) function via activation of the NF-kappa B (NF-kB) pathway also plays a critical role in the onset of labor. Activation of uterine NF-kB inhibits uterine PR action leading to a loss of P4 maintained uterine quiescence and the onset of uterine contraction. In this proposal we test the hypothesis that NF-:B activation and a withdrawal of PR action play a critical role in alleviating uterine quiescence during the final trimester of pregnancy through inhibition of the anti-contractile action of uterine caspase-3. Although activation of caspase-3 is typically associated with the onset of apoptosis, recent studies have identified caspase-3 as a negative regulator of myocyte contractility in cardiac, skeletal and smooth muscle without resulting in cell death. Caspase-3 activity in the contractile myocyte has been associated with degradation of the cytoplasmic contractile apparatus. However upon NF-kB mediated caspase-3 removal, the quiescent myocytes are amenable to cytoplasmic reconstitution and regain their contractile ability. We hypothesize during pregnancy robust caspase-3 levels maintain the uterus in a quiescent state through degradation of the uterine myocyte contractile architecture. Activation of uterine NF-kB and a withdrawal of PR action decreases myometrial caspase-3 levels, permitting reconstitution of the myocyte contractile apparatus, enhanced myometrial contractility and the onset of labor. We have made the observation that the removal of uterine caspase-3 activity is mediated by up-regulation of anti-caspase-3 signaling. Co- incident with caspase-3 clearance we also observe reconstitution of the uterine myocyte contractile apparatus. The proposed research is to test the hypothesis and understand the mechanisms involved in the process whereby uterine NF-kB activation and a PR functional withdrawal serve as vital steps in the loss of uterine quiescence through inhibition of caspase-3 activity in the pregnant uterus as term approaches.
The appropriate timing of the onset of labor is critical to a successful pregnancy with devastating consequences resulting to both the mother and child with the onset of preterm labor. However the mechanisms that lead to the onset of both normal term and pre-term labor still remain a mystery. The proposed research is to understand the mechanisms involved in the onset of normal term labor so we can learn to detect and inhibit inappropriate triggering of these events that may lead to the onset of pre-term labor.
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