Molecular Mechanisms of Parturition

描述(由申请人提供)：分娩，分娩的过程，是一种基本的生物学功能，其分子机制尚不清楚。这项研究建议的长期目标是加强我们对控制分娩开始和进展的过程的了解，特别是在宫颈中发生的促进软化和成熟的事件。这些研究将为未来的遗传学研究奠定基础，这些研究旨在识别使妇女容易发生宫颈功能不全或早产的基因多态/突变，以及识别对早产有积极预测的生化标记物。具体目标1的研究将集中于鉴定5a-还原酶1基因中的序列，该基因在怀孕和分娩期间协调该基因独特的细胞和时间特异性表达。在特定目标2中概述的研究将加强我们对转录、翻译和结构变化的理解，这些变化介导了宫颈软化，这是一个不同于宫颈成熟的过程。在特定目标3中概述的研究将通过识别招募到宫颈的细胞和这些细胞的激活时间来澄清我们对炎症过程在启动正常宫颈成熟中所起的作用的理解。对特定目的4的研究将加深我们对宫颈上皮在促进分娩时宫颈重塑中所起作用的理解，特别是通过紧密连接蛋白和上皮分化来调节细胞旁运输。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。在北美，早产影响高达14%的怀孕。妊娠37周前出生的早产儿有更高的婴儿死亡率、呼吸并发症和终身医学并发症的风险，因此我们旨在预防早产的研究对公共卫生具有重要意义。

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.