Molecular and Genomic Mechanisms in the Biology of Pregnancy and Parturition

项目总结/摘要 在这个新的计划项目中，我们将利用全面的全球基因组方法（RNA测序[RNA- seq]、全局运行测序[GRO-seq]和染色质免疫沉淀测序[ChIP-seq]）， 了解足月和早产的生物学机制。这个应用程序是及时的，因为 基因组技术的巨大进步与尖端的计算工具相结合，这些工具具有戏剧性的， cally推进了我们对各种生物系统中信号调节基因转录的理解。 这些检测产生的全局视图提供了一个独特的信息丰富的生物学视角， 可以通过一次分析一个甚至几个基因来实现。我们建议利用这些最先进的 技术，以深入了解基因组和表观基因组机制， 调节子宫肌层静止-收缩、宫颈功能-扩张和维持屏障 子宫颈的功能，以保护怀孕免受微生物入侵，防止早产。的 P01包括四个相互关联的项目：项目1： 怀孕和分娩（Carole R。项目2：雌激素受体a乙酰化的功能作用 在子宫（W. Lee Kraus）;项目3：子宫颈中雌激素受体激活的基因组后果 （R. Ann Word）;项目4：宫颈上皮屏障对上行感染的保护机制， 早产（Mala S. Mahendroo），由三个核心支持：行政核心（Mendelson）;基因组学 和计算核心（克劳斯）;人体组织和生物流体采集实验室核心（Word）。的 这些项目的目标是：项目1 -确定基因和机制，这些行动的基础 孕酮（P4），通过孕酮受体亚型，PR-A和PR-B，对炎症和“收缩”基因 表达，并表征介导子宫肌层静止的染色质修饰， 伴随着增强的收缩基因表达，导致足月和早产;项目2 -实现一个 更好地了解雌激素信号通过雌激素受体a（ER a）在女性的生物学 通过阐明ER α乙酰化在妊娠和分娩期间生殖道的功能中的作用， 妊娠女性的子宫和宫颈以及ER α乙酰化控制的分子机制 这些组织中ER α依赖的基因调控;项目3 -了解PR和PR的机制。 ER相互作用，改变基因表达，妊娠期长度和子宫颈的结构完整性， 妊娠、宫颈成熟和分娩;项目4 -利用基因组、细胞生物学和生物化学 方法，以促进我们的机制，透明质酸（HA）提供免疫- 保护和上皮屏障功能，以及分子机制， HA合成酶2受到调节。我们建议，这些相互关联的项目，由一个高度互动的 研究团队的努力，将实现我们降低早产发生率的长期目标。

PROJECT SUMMARY/ABSTRACT In this new program project, we will utilize comprehensive global genomic approaches (RNA sequencing [RNA- seq], global run-on sequencing [GRO-seq], and chromatin immunoprecipitation sequencing [ChIP-seq]) to understand the biological mechanisms for term and preterm birth. This application is timely, because of the huge advances in genomic technologies combined with cutting-edge computational tools, which have dramati- cally advanced our understanding of signal-regulated gene transcription in a wide variety of biological systems. The global views generated by these assays provide a uniquely informative biological perspective that cannot be achieved by analyzing one or even a few genes at a time. We propose to utilize these state-of-the-art techniques to develop an in-depth understanding of the genomic and epigenomic mechanisms that underlie the regulation of myometrial quiescence-contractility, cervical competency-dilation, and that maintain barrier function of the cervix to protect the pregnancy against invading microorganisms and prevent prematurity. The P01 includes four interrelated projects: Project 1: Epigenetic Regulation of Myometrial Contractility in Pregnancy and Labor (Carole R. Mendelson); Project 2: Functional Roles of Estrogen Receptor a Acetylation in the Uterus (W. Lee Kraus); Project 3: Genomic Consequences of Estrogen Receptor Activation in the Cervix (R. Ann Word); Project 4: Mechanisms of Cervical Epithelial Barrier Protection Against Ascending Infection and Preterm Birth (Mala S. Mahendroo), supported by three cores: Administrative Core (Mendelson); Genomics and Computational Core (Kraus); Human Tissue and Biological Fluid Acquisition Laboratory Core (Word). The goals of these projects are: Project 1 - to define the genes and mechanisms that underlie the actions of progesterone (P4), via progesterone receptor isoforms, PR-A and PR-B, on inflammatory and `contractile' gene expression, and to characterize the chromatin modifications that mediate myometrial quiescence and accompany enhanced contractile gene expression leading to term and preterm labor; Project 2 - to achieve a better understanding of the biology of estrogen signaling through estrogen receptor a (ERa) in the female reproductive tract during pregnancy and parturition by elucidating the role of ERa acetylation in the function of the uterus and cervix of pregnant females and the molecular mechanisms by which ERa acetylation controls ERa-dependent gene regulation in these tissues; Project 3 - to understand the mechanisms by which PRs and ERs interact to alter gene expression, gestational length, and structural integrity of the cervix during pregnancy, cervical ripening and parturition, and; Project 4 – to utilize genomic, cell biological and biochemical approaches to advance our understanding of the mechanisms by which hyaluronan (HA) provides immune- protection and epithelial barrier function in the pregnant cervix, as well as the molecular mechanisms whereby HA synthase 2 is regulated. We propose that these interrelated projects, carried out by a highly interactive research team, will achieve our long-range goal of reducing the incidence of preterm birth.