Initiation of Human Labor: Prevention of Prematurity

人类分娩的开始：预防早产

• 批准号: 8442190
• 负责人: CAROLE R MENDELSON
• 金额: $ 119.43万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442190
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Birth; Cervical; Cervical Ripening; Cervix Uteri; Enzymes; Epigenetic Process; Event; Fetus; Functional disorder; Gene Targeting; Genes; Genetic; Goals; Human; Hyaluronan; Hyaluronidase; Incidence; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Lead; Live Birth; Mammals; Molecular; Myometrial; Neonatal Mortality; Nuclear Receptors; Pathway interactions; Physiological; Physiology; Play; Pregnancy; Premature Birth; Premature Labor; Prevention; Progesterone; Regulation; Research; Role; Series; Signal Pathway; Signal Transduction; Testing; Up-Regulation; base; hyaluronan synthase 1; insight; neonatal morbidity; novel; premature; prevent; programs; therapeutic development; transcription factor; trend; uterine contractility

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.

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，在过去的二十年中稳步增长，现在接近所有活产的约13％。这种令人震惊的趋势部分归因于我们对整个怀孕期间保持宫颈完整性和子宫静止的途径的不完全理解，以及促进宫颈成熟并增加子宫收缩力的途径，导致劳动。越来越多的证据表明，术语和早产均与炎症反应有关，并且在整个怀孕的大部分时间里，孕酮（P4）通过IT核受体（PR）的抗炎作用阻止了这种反应。该提案的中心主题仍然是阐明导致在学期和早产的分子和细胞机制的阐明。该主题是基于总体假设，即人类和其他哺乳动物中自发劳动的开始是由一系列一致的生化和分子事件引起的，这些事件在炎症反应途径的上调和PR功能下降时最终导致。尽管早产劳动可能有许多原因，但我们建议促进子宫收缩性过早增加，宫颈成熟和驱逐胎儿的信号传导途径与期限的信号通路相似。因此，了解导致分娩的机制应为开发治疗策略的发展提供重要的见解，以阻止这些信号机制并防止早产。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）进一步定义遗传和表观遗传机制，P4/PR抑制怀孕期间的肌层收缩性，炎症信号通过该遗传和表观遗传机制上调了收缩基因并抑制PR的功能（2），以增强我们对疗程的影响，从而增强我们对疗程的理解（HA）的作用，从而促进质量良好的基因效果，从而促进质量良好的质量，从而产生质量的质量，从而产生了质量的影响。调节酶，透明质酸合酶2以及HA降解酶，透明质酸酶的表达改变，（3），（3）通过涉及PRS，ER的转录网络来阐明宫颈成熟和扩张的调节，该网络涉及PRS，ER，ER和新型宫颈转录因子MITF-CX和（4）的疗法，该疗法是usitigy andotic and protiction intodicity protiction to protiction mitf-cx和4）怀孕期间的子宫颈和分娩期间具有一组共同的分子事件，这些事件在早产和术语分娩的生理学中起着至关重要的作用。我们建议这些相互关联的项目由高度互动的研究团队实现，将实现该计划的远程目标，并有助于减少早产的发生率。