Post-translational Modification of Cx43 Regulates Myometrial Quiescence

项目总结摘要 早产是导致早产儿残疾和死亡的主要医学问题。治疗方法 管理早产是不合时宜和无效的。目前使用的酵解疗法超过48小时都不能令人满意，而且 没有一种是FDA批准的。早产对非裔美国女性的影响比高加索女性更常见。 我们试图了解导致早产和由此导致的早产的子宫肌层松弛功能障碍。 出生。我们的中心假设是，一氧化氮是由微血管内皮细胞在子宫肌层内局部产生的。 细胞因机械拉伸而增加流向扩张子宫的血流量。一氧化氮S-亚硝酸盐Cx43在 肌肉细胞。Cx43 S亚硝化促进C末端磷酸化，使Cx43处于半通道状态，并 有利于肌肉细胞的静止。在分娩时，半沟会形成缝隙连接。间隙连接是激活的功能之一 子宫肌层。促进缝隙连接蛋白43的S亚硝化为宫缩的发生提供了独特的靶点。翻译 如果我们要发现和开发人类妊娠组织的独特机制，那么在人类妊娠组织中的方法是必不可少的。 妊娠期子宫静止及其在早产中的调节失调。

PROJECT SUMMARY ABSTRACT Preterm birth is a major medical problem resulting in disability and death for very preterm infants. Therapeutic approaches to manage preterm labor are off-label and ineffective. No tocolytic therapy in use today is satisfactory beyond 48 hours, and none are FDA approved. Preterm labor more often impacts African American women than their Caucasian counterparts. We seek to understand the dysfunctional relaxation of the myometrium that leads to preterm labor and resulting preterm birth. Our central hypothesis is that nitric oxide is generated locally within the myometrium by microvascular endothelial cells as a result of mechanical stretch and increased blood flow to the expanding uterus. Nitric oxide S-nitrosates Cx43 in the muscle cell. Cx43 S-nitrosation promotes C-terminal phosphorylation that holds Cx43 in its hemichannel state and favors muscle cell quiescence. Hemichannels form gap junctions at the time of labor. Gap junctions are a feature of activated myometrium. Promoting connexin 43 S-nitrosation offers a unique target for tocolytic development. Translational approaches in human pregnancy tissues are essential if we are to discover and exploit the unique mechanisms that subserve uterine quiescence during pregnancy and their dysregulation in preterm labor.