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

描述（由申请人提供）：在怀孕的最后三个月，子宫经历了一个显著的转变，从一个相对静止的状态到一个活跃的收缩单位。妊娠子宫收缩的启动与催产素受体增加、间隙连接增加和宫颈成熟有关。除了人类之外，大多数哺乳动物体内循环中黄体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nf - κ B （NF-kB）途径抑制子宫黄体酮受体（PR）功能也在分娩过程中起着关键作用。子宫NF-kB的激活抑制子宫PR的作用，导致P4的丢失，维持子宫静止和子宫收缩的发生。在本研究中，我们验证了NF-:B的激活和PR作用的退出通过抑制子宫caspase-3的抗收缩作用在妊娠晚期缓解子宫静止中起关键作用的假设。尽管caspase-3的激活通常与细胞凋亡的发生有关，但最近的研究发现，caspase-3是心肌、骨骼肌和平滑肌中肌细胞收缩性的负调节因子，而不会导致细胞死亡。收缩性肌细胞中的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，静止的肌细胞可以进行细胞质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NF-kB的激活和PR作用的退出降低了肌层caspase-3水平，允许肌细胞收缩装置的重建，增强了肌层收缩力和分娩的开始。我们观察到子宫caspase-3活性的去除是通过上调抗caspase-3信号通路介导的。与caspase-3清除同时，我们还观察到子宫肌细胞收缩器的重建。该研究旨在验证这一假设，并了解子宫NF-kB激活和PR功能戒除过程中所涉及的机制，这一过程是通过抑制妊娠子宫中caspase-3活性而导致子宫平静期丧失的重要步骤。

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.