Initiation of Human Labor: Prevention of Prematurity

人类分娩的开始：预防早产

• 批准号: 6867658
• 负责人: CAROLE R MENDELSON
• 金额: $ 149.1万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867658
• 关键词: clinical research; disease /disorder prevention /control; molecular biology; premature labor

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.

成功分娩需要子宫肌层和子宫颈发生一系列事件，这已被广泛研究多年。然而，早产仍然是妊娠的重要并发症，具有严重的个人和社会后果。子宫肌从长期静止状态中释放和子宫颈重塑的分子控制仍然难以捉摸。这个计划项目的长期目标是阐明调节这些过程的分子机制，包括足月分娩和早产。为此，提出了四个项目。第一个项目探讨了人类胎儿肾上腺在分娩中的潜在作用。具体来说，它将确定促肾上腺皮质激素释放激素激活胎儿肾上腺的分子机制，从而导致胎儿分娩时的前馈级联反应。将使用来自人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酮受体（PR）功能产生负面影响的生理和生化事件，基于子宫静止取决于PR转录活性增加和NF-κ B引起子宫静止释放的假设。具体来说，目标将定义的作用，表面活性蛋白在劳动力的启动，通过NF-κ B的信号传导机制，在长期的子宫，孕酮和NF-κ B的调节参与子宫肌层静止/收缩的靶基因的共激活因子下降的机制，使用小鼠和人类模型。第三个项目探讨宫颈重塑的过程，基于基质糖胺聚糖透明质酸（HA）与宫颈变化一致的显着变化。使用小鼠模型和人体组织，目的是确定控制HA合成的酶和HA结合蛋白的调节元件，影响HA在基质中的功能;将测试这种调节在宫颈机能不全或早产妇女中改变的假设。在第四个项目中，一个特定的转录因子，MiTF，在宫颈变化的作用，在任期内将得到解决，基于一个新的组织特异性亚型显着减少与劳动力的发病。将研究这种亚型在人子宫颈和子宫肌层中的调控，包括鉴定其在特定细胞类型中转录激活的正调控因子和负调控因子。将确定宫颈基质细胞中该转录因子的靶基因。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，以实现本提案的长期目标。