Molecular and Genomic Mechanisms in the Biology of Pregnancy and Parturition

项目摘要/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]、全球连续测序[GRO-SEQ]和染色质免疫沉淀测序[CHIP-SEQ])来 了解足月和早产的生物学机制。这个应用程序很及时，因为 基因组技术的巨大进步与尖端的计算工具相结合，极大地促进了我们对各种生物系统中信号调控基因转录的理解。 这些分析产生的全球视角提供了一种独特的信息丰富的生物学视角，而不是 通过一次分析一个甚至几个基因来实现。我们打算利用这些最先进的技术 深入了解构成基因组和表观基因组机制的技术 子宫肌层静止-收缩、宫颈能力-扩张和维持屏障的调节 宫颈的功能是保护孕妇免受微生物侵袭，防止早产。这个 P01包括四个相互关联的项目：项目1：子宫肌层收缩的表观遗传学调节 怀孕和分娩(卡罗尔·R·门德尔森)；项目2：雌激素受体α乙酰化的功能作用 子宫中(W.Lee Kraus)；项目3：子宫颈雌激素受体激活的基因组后果 (R.Ann Word)；项目4：宫颈上皮屏障预防上升感染的机制和 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(Kraus)；人体组织和生物流体获取实验室核心(WORD)。这个 这些项目的目标是：项目1--确定作为行动基础的基因和机制 孕酮(P4)，通过孕酮受体亚型PR-A和PR-B，在炎性和收缩基因上 表达，并表征介导子宫肌层静止和染色质修饰 伴随着收缩基因表达增强导致足月和早产；项目2-实现 更好地了解通过雌激素受体α(ERα)传递雌激素信号的生物学 通过阐明ER-α乙酰化在细胞周期调控中的作用探讨妊娠和分娩过程中的生殖道 妊娠女性子宫和宫颈及ERα乙酰化调控的分子机制 这些组织中ER-α依赖的基因调控；项目3-了解PR和 雌激素受体相互作用改变基因表达、妊娠长度和宫颈的结构完整性 怀孕、宫颈成熟和分娩；项目4--利用基因组、细胞生物学和生化 提高我们对透明质酸(HA)提供免疫保护机制的认识的途径 妊娠宫颈的保护和上皮屏障功能及其分子机制 HA合成酶2受调控。我们建议，这些相互关联的项目，由高度互动的 研究团队，将实现我们降低早产发生率的长远目标。

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 dramatically 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 α 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 α (ERα) in the female reproductive tract during pregnancy and parturition by elucidating the role of ERα acetylation in the function of the uterus and cervix of pregnant females and the molecular mechanisms by which ERα acetylation controls ERα-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.