Initiation of Human Labor: Prevention of Prematurity

成功的分娩需要子宫肌层和宫颈的一系列事件，这些事件已经被广泛研究了很多年。然而，早产仍然是妊娠的一个重要并发症，会给个人和社会带来严重的后果。对子宫肌肉从长期静止状态中释放出来和宫颈重塑的分子控制仍然难以捉摸。该计划项目的长期目标是阐明调节这些过程的分子机制，包括足月和早产。为此，提出了四个项目。第一个项目解决了人类胎儿肾上腺在分娩中的潜在作用。具体地说，它将确定促肾上腺皮质激素释放激素激活胎儿肾上腺导致前馈级联反应的分子机制，最终导致胎儿的分娩。将使用来自人类胎儿肾上腺新皮质和胎儿区的组织和细胞。第二个项目侧重于引起炎症反应和对孕激素受体(PR)功能产生负面影响的生理和生化事件，基于子宫静止依赖于PR转录活性增加和核因子-kappaB导致子宫静止释放的假设。具体地说，AIMS将确定表面活性蛋白在分娩启动中的作用，它们通过核因子-kappaB的信号机制，足月子宫中辅助激活因子下降的机制，以及孕酮和核因子-kappaB对涉及肌层静止/收缩的靶基因的调节，使用小鼠和人类模型。第三个项目探索宫颈重塑的过程，基于发现的与足月宫颈变化相一致的基质糖胺聚糖透明质酸(HA)的显著变化。利用小鼠模型和人体组织，AIMS将确定控制HA合成的酶中的调节元件，以及基质中影响HA功能的HA结合蛋白；这一调节在宫颈功能不全或早产妇女中发生改变的假设将得到验证。在第四个项目中，一种特定的转录因子MITF在足月宫颈变化中的作用将被解决，基于一种新的组织特异性亚型随着分娩的开始而急剧减少。该异构体在人类宫颈和子宫肌层中的调节将被研究，包括在特定细胞类型中识别其转录激活的正调节因子和负调节因子。该转录因子在宫颈基质细胞中的靶基因将被确定。研究人员是一个高度互动的研究团队，四个研究项目中描述的研究被整合和协调，以实现这一提案的长期目标。

Successful parturition requires a sequence of events in myometrium and cervix that has been extensively studied over many years. Yet, preterm labor remains a significant complication of pregnancy, with severe individual and societal consequences. The molecular controls for the release of the uterine muscle from its protracted quiescent state and the remodeling of the cervix remain elusive. The long-range goals of this Program Project are to elucidate the molecular mechanisms regulating these processes, both in term and preterm labor. To this end, four projects are proposed. The first project addresses the potential role of the human fetal adrenal in parturition. Specifically, it will determine molecular mechanisms through which corticotropin-releasing hormone activates the fetal adrenal gland to cause a feed-forward cascade culminating in delivery of the fetus. Tissues and cells from human fetal adrenal neocortex and fetal zone will be used. The second project focuses on the physiological and biochemical events that cause an inflammatory response and negatively impact progesterone receptor (PR) function, based on postulates that uterine quiescence depends on increased PR transcriptional activity and NF-kappaB causes release from uterine quiescence. Specifically, the aims will define the role of surfactant proteins in the initiation of labor, their signaling mechanisms via NF-kappaB, mechanisms for the decline in coactivators in the term uterus, and progesterone and NF-kappaB regulation of target genes involved in myometrial quiescence/contractility, using both murine and human models. The third project explores the process of cervical remodeling, based on significant changes found in the matrix glycosaminoglycan hyaluronan (HA) coincident with cervical changes at term. Using murine models and human tissues, the aims will identify regulatory elements in the enzymes controlling HA synthesis and HA-binding proteins affecting HA function in the matrix; the hypothesis that this regulation is altered in women with cervical incompetence or preterm labor will be tested. In the fourth project the role of a specific transcription factor, MiTF, in cervical changes at term will be addressed, based on the finding that a novel tissue-specific isoform decreases dramatically with labor onset. The regulation of this isoform in human cervix and myometrium will be studied, including identifying positive and negative regulators of its transcriptional activation in specific cell types. Target genes of this transcription factor in cervical stromal cells will be identified. The investigators are a highly interactive research team, and the studies described in the four research projects are integrated and coordinated to achieve the long-range goals of this proposal.