Molecular Mechanisms of Parturition

描述（由申请人提供）：分娩是一种重要的生物学功能，其分子机制尚不清楚。这项研究计划的长期目标是加强我们对控制分娩开始和进展的过程的理解，特别是发生在子宫颈的事件，以促进软化和成熟。这些研究将为未来的基因研究奠定基础，这些研究旨在确定使妇女易患宫颈功能不全或早产的基因多态性/突变，以及确定能积极预测早产的生化标志物。Specific Aim 1的研究将集中于鉴定5a-还原酶1型基因中的序列，该基因在妊娠和分娩时协调该基因的独特细胞和时间特异性表达。具体目标2中概述的研究将增强我们对介导颈椎软化的转录、翻译和结构变化的理解，这一过程不同于颈椎成熟。在Specific Aim 3中概述的研究将通过识别子宫颈募集的细胞和这些细胞的激活时间，阐明我们对炎症过程在正常子宫颈成熟起始过程中所起作用的理解。Specific Aim 4的研究将增强我们对宫颈上皮在促进分娩时宫颈重塑中的作用的理解，特别是通过紧密连接蛋白和上皮分化调节细胞旁运输。从这项研究中获得的见解将进一步加深我们对分娩过程的理解，并导致预防早产的治疗方法，早产影响了北美高达14%的怀孕。妊娠37周前出生的早产儿婴儿死亡率、呼吸并发症和终生医疗并发症的风险较高，因此我们旨在预防早产的研究与公共卫生具有重要关系。

DESCRIPTION (provided by applicant): Parturition, the process of giving birth, is an essential biological function for which the molecular mechanisms are poorly understood. The long-term goals of this research proposal are to enhance our understanding of the processes that control the initiation and progression of parturition, specifically the events that occur in the cervix to facilitate softening and ripening. These studies will lay the groundwork for future genetic studies aimed at identifying gene polymorphisms/mutations that predispose women to cervical incompetence or preterm birth as well as for the identification of biochemical markers for positive prediction of preterm labor. Studies in Specific Aim 1 will focus on the identification of sequences in the 5a-reductase type 1 gene that orchestrate the unique cell and temporal specific expression of this gene in pregnancy and parturition. Studies outlined in Specific Aim 2 will enhance our understanding of transcriptional, translational and structural changes that mediate cervical softening, a process that is distinct from cervical ripening. The studies outlined in Specific Aim 3 will clarify our understanding of the role inflammatory processes play in initiation of normal cervical ripening by identifying cells recruited to the cervix and the timing of activation of these cells. Studies in Specific Aim 4 will enhance our understanding of the role cervical epithelial play in facilitating cervical remodeling at parturition, specifically the regulation of paracellular transport by tight junction proteins and epithelial differentiation. Insights gained from this research will further our understanding of the parturition process and lead to therapies for the prevention of preterm birth which affects up to 14% of pregnancies in North America. Premature infants born before 37 weeks gestation are at a higher risk of infant mortality, breathing complications and suffering lifelong medical complications thus our studies aimed at preventing preterm labor are of significant relevance to public health.