Initiation of Human Labor: Prevention of Prematurity

描述（由申请人提供）：早产是美国新生儿发病率和死亡率的主要原因，在过去的二十年里，这一比例稳步上升，目前已接近所有活产婴儿的13%。这种令人担忧的趋势部分是由于我们对整个怀孕期间维持宫颈完整性和子宫静止的途径以及促进宫颈成熟和增加子宫收缩力导致分娩的途径的不完全理解。越来越多的证据表明，足月分娩和早产都与炎症反应有关，并且在整个怀孕期间，通过孕酮（P4）的抗炎作用，通过其核受体（PR）来预防炎症反应。该建议的中心主题仍然是阐明导致足月和早产分娩启动的分子和细胞机制。这一主题基于以下总体假设：人类和其他哺乳动物中自发分娩的启动是由一系列协调一致的生化和分子事件引起的，这些事件最终导致炎症反应途径的上调和PR功能的降低。虽然早产可能有许多原因，但我们认为促进子宫收缩力过早增加、宫颈成熟和胎儿排出的信号通路与足月时相似。因此，了解导致足月分娩的机制应该为阻断这些信号传导机制和预防早产的治疗策略的发展提供重要的见解。为了实现这些目标，提出了四个相互关联的项目和两个核心。这些项目的目标是：（1）为了进一步确定遗传和表观遗传机制，其中P4/PR在妊娠期间抑制子宫肌层收缩性，并且炎症信号传导通过其上调收缩基因并抑制PR功能导致分娩，（2）通过阐明子宫颈的作用，加强我们对透明质酸（HA）在子宫颈成熟中作用的认识-关键调控酶透明质酸合成酶2的特异性基因靶向，以及HA降解酶透明质酸酶的表达改变，（3）阐明通过涉及PR、ER和新型宫颈转录因子MiTF-CX的转录网络对宫颈成熟和扩张的调控，以及（4）检验妊娠和分娩期间子宫和子宫颈中的生理和病理炎症反应共享一组共同的分子事件的假设，所述分子事件在早产和足月分娩的生理学中起关键作用。我们建议，这些相互关联的项目，由一个高度互动的研究团队进行，将实现该计划的长期目标，并有助于减少早产的发生率。

DESCRIPTION (provided by applicant): Preterm birth, the major cause of neonatal morbidity and mortality in the U.S., has increased steadily over the past two decades and now approaches ~13% of all live births. This alarming trend is due, in part, to our incomplete understanding of the pathways that maintain cervical integrity and uterine quiescence throughout pregnancy as well as those that promote cervical ripening and increased uterine contractility leading to labor. There is increasing evidence that both term and preterm labor are associated with an inflammatory response and that this is prevented throughout most of pregnancy by the anti-inflammatory actions of progesterone (P4) acting through it nuclear receptor (PR). The central theme of this proposal remains the elucidation of the molecular and cellular mechanisms that lead to the initiation of parturition, both at term and preterm. This theme is based on the overall hypothesis that the initiation of spontaneous labor in humans and in other mammals, is caused by a concerted series of biochemical and molecular events that culminate in an upregulation of inflammatory response pathways and a decrease in PR function. Although, preterm labor may have numerous causes, we propose that the signaling pathways that promote premature increase in uterine contractility, cervical ripening and expulsion of the fetus are similar to those at term. Thus, understanding the mechanisms leading to parturition at term should provide important insight into the development of therapeutic strategies to block these signaling mechanisms and prevent preterm labor. To achieve these goals, four interrelated projects and two cores are proposed. The goals of these Projects are: (1) To further define the genetic and epigenetic mechanisms whereby P4/PR inhibits myometrial contractility during pregnancy and by which inflammatory signaling upregulates contractile genes and represses PR function leading to labor, (2) to enhance our understanding of the role of hyaluronan (HA) in cervical ripening through elucidation of the effects of cervix-specific gene targeting of the key regulatory enzyme, hyaluronan synthase 2, and altered expression of HA degradative enzymes, hyaluronidases, (3) to elucidate the regulation of cervical ripening and dilation through a transcriptional network involving PRs, ERs, and the novel cervical transcription factor MiTF-CX, and (4) to test the hypothesis that physiological and pathological inflammatory responses in the uterus and cervix during pregnancy and parturition share a common set of molecular events that play crucial roles in the physiology of preterm and term parturition. We propose that these interrelated projects, carried out by a highly interactive research team, will achieve the long-range goals of this Program and contribute to a reduction in the incidence of preterm birth.