Caspase-3 Maintains Uterine Quiescence in a PR and NF-kappa B Dependent Manner

描述(申请人提供)：在怀孕的最后三个月，子宫经历了从相对静止的状态到活跃的收缩单元的显着转变。妊娠子宫的收缩准备与催产素受体增加、缝隙连接增加和宫颈成熟有关。在大多数哺乳动物中，但不包括人类，循环中孕酮水平的急剧下降也预示着分娩的开始。越来越多的证据表明，通过激活核因子-kappaB(NF-kB)途径抑制子宫孕酮受体(PR)的功能也在分娩的开始中起着关键作用。子宫核因子-kB的激活抑制了子宫的PR作用，导致P4的丧失，维持子宫的平静和子宫收缩的开始。在这项建议中，我们测试了一种假设，即核因子：B的激活和PR作用的取消在妊娠最后三个月通过抑制子宫caspase-3的抗收缩作用而在缓解子宫静止方面发挥关键作用。虽然caspase-3的激活通常与细胞凋亡的开始有关，但最近的研究发现，caspase-3是心肌、骨骼肌和平滑肌细胞收缩能力的负调节因子，而不会导致细胞死亡。收缩心肌细胞中的caspase-3活性与细胞质收缩装置的降解有关。然而，在NF-kB介导的caspase-3去除后，静止的心肌细胞可以进行胞浆重建，并恢复其收缩能力。我们假设，在怀孕期间，强大的caspase-3水平通过降解子宫肌细胞收缩结构来维持子宫处于静止状态。子宫核因子-kB的激活和PR作用的取消降低了子宫肌层caspase-3的水平，允许肌细胞收缩装置的重建，增强了子宫肌层的收缩能力，并开始分娩。我们观察到，子宫caspase-3活性的去除是通过上调抗caspase-3信号而介导的。在caspase-3清除的同时，我们还观察到子宫肌细胞收缩装置的重建。这项拟议的研究旨在检验这一假说，并了解子宫核因子-kB激活和PR功能取消作为关键步骤，通过抑制妊娠子宫中caspase-3的活性来消除子宫静止的过程。

DESCRIPTION (provided by applicant): 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.