Determination of Fetal Gene Expression in Women with Preterm & Term Birth

早产妇女胎儿基因表达的测定

• 批准号: 8751061
• 负责人: Neeta L Vora
• 金额: $ 7.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751061
• 关键词: Amniotic Fluid; Animal Model; Antioxidants; Biological Markers; Birth; Blood; Blood Circulation; Caring; Cell Line; Cells; Cessation of life; Clinical; Corticotropin; Corticotropin-Releasing Hormone; Data; Development; Discipline of obstetrics; Disease; Fetal Membranes; Fetus; Functional disorder; Future; Gene Expression; Genes; Genetic; Genome; Genomics; Glutamate Receptor; Goals; Hormone Antagonists; Hydrocortisone; Hypothalamic structure; Infant; Infection; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Knowledge; Lead; Literature; Maps; Measures; Medical; Methods; Molecular Profiling; Neuropeptides; Nitric Oxide Synthase Type I; PRKCA gene; Pathway interactions; Pattern; Pharmaceutical Preparations; Phospholipase C; Physiological; Placenta; Polymerase Chain Reaction; Pregnancy; Premature Birth; Premature Infant; Prevention; Prevention strategy; Primary Prevention; Production; Prospective Studies; Protein Kinase C; Public Health; Publishing; RNA; Regulation; Regulator Genes; Research; Resolution; Risk; Role; Scientist; Second Pregnancy Trimester; Sheep; Specificity; Specimen; Stress; Supplementation; Term Birth; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissue-Specific Gene Expression; Umbilical Cord Blood; United States; United States Food and Drug Administration; Up-Regulation; Woman; base; cost; disability; fetal; fetal medicine; hypothalamic-pituitary-adrenal axis; infant morbidity/mortality; innovation; multidisciplinary; new therapeutic target; novel; premature; prevent; prospective; public health relevance; receptor; response; screening; therapeutic target; tool

DESCRIPTION (provided by applicant): Preterm birth is a major public health concern defined as delivery prior to 37 completed weeks of gestation. Each year, up to 360,000 pregnancies deliver preterm. Preterm infants are at greater risk of death and disability than are term infants. Despite decades of research, primary prevention strategies to reduce or eliminate spontaneous preterm birth (sPTB) are lacking. The proposed study will explore the role of fetal hypothalamic-pituitary-adrenal (HPA) axis activation in sPTB and identify potential new therapeutic targets for primary sPTB prevention. The objective of this proposal is to determine whether sPTB is associated with differential fetal HPA axis gene expression compared to term births. Our central hypothesis is that fetuses that are delivered preterm have more up-regulation of HPA axis gene expression compared to those that are delivered at term. We formulated our central hypothesis based on published literature showing that corticotrophin-releasing hormone (CRH), a hypothalamic neuropeptide that regulates HPA axis activity, is integral to the regulation of labor. We will test our central hypothesis by completing two specific aims: 1: To quantify second trimester fetal expression of the key regulatory genes of the HPA axis using previously collected second trimester amniotic fluid specimens in spontaneous preterm and term births; 2) To prospectively measure fetal HPA axis-associated gene expression in both the fetal (amniotic fluid and umbilical cord blood) and maternal (blood) compartments obtained at the time of delivery of spontaneously preterm and term infants. These aims will be achieved through a retrospective and prospective analysis of amniotic fluid supernatant from women with sPTB (<34 weeks) or spontaneous term birth (>37 weeks). Fetal HPA axis gene expression will be quantified via real- time polymerase chain reaction (RT-PCR) after extraction of cell-free fetal RNA. In addition, whole genome microarray expression arrays will be used to identify other potential fetal pathways up or down-regulated in sPTB. Fetal biomarkers related to sPTB will be identified in the prospectively collected maternal blood by RT-PCR. The approach is innovative because our proposal is the first to use amniotic fluid supernatant in previously collected and prospectively collected deliveries to isolate cffRNA and measure fetal HPA axis-associated gene expression in sPTB and term birth. The proposed research is significant because identifying differential gene expression of the fetal HPA axis among pregnancies complicated by sPTB will allow us to develop new strategies to test for primary sPTB prevention. Ultimately, such knowledge has the potential to inform novel therapies to prevent sPTB.

描述（由申请人提供）：早产是在妊娠37周之前定义为交货的主要公共卫生问题。每年，多达360,000例怀孕提供早产。早产儿的死亡和残疾风险要比术语婴儿更大。 尽管进行了数十年的研究，但仍缺乏减少或消除自发早产（SPTB）的主要预防策略。拟议的研究将探讨SPTB中胎儿下丘脑 - 垂体 - 肾上腺（HPA）轴激活的作用，并确定预防原发性SPTB的潜在新治疗靶标。该提案的目的是确定SPTB是否与胎儿HPA轴基因表达相比是否与期限出生相比。我们的中心假设是，与术语交付的胎儿相比，早产的胎儿对HPA轴基因表达的上调更多。我们基于发表的文献提出了中心假设，表明皮质营养蛋白释放激素（CRH）是一种调节HPA轴活动的下丘脑神经肽，是劳动调节的组成部分。 我们将通过完成两个具体目的来测试中心假设：1：使用先前收集的自发性早产和期限出生的妊娠中期羊水标本来量化HPA轴关键调节基因的关键调节基因； 2）在胎儿（羊水和脐带血液）和胎儿（血液）（血液）室中，在自发早产和年前婴儿分娩时获得的胎儿HPA轴相关基因表达和孕产妇（血液）隔室均与胎儿HPA相关的基因表达。这些目标将通过对SPTB（<34周）或自发期限出生（> 37周）的女性的回顾性和前瞻性分析来实现。在提取无细胞胎儿RNA后，将通过实时聚合酶链反应（RT-PCR）对胎儿HPA轴基因表达进行定量。此外，整个基因组微阵列表达阵列将用于识别SPTB中上调或下调的其他潜在胎儿途径。 RT-PCR将在前瞻性收集的母体血液中鉴定出与SPTB相关的胎儿生物标志物。该方法具有创新性，因为我们的建议是在先前收集的和前瞻性收集的递送中使用羊水上清液，以分离cffrna并测量SPTB和术语出生中与胎儿HPA轴相关的基因表达。拟议的研究很重要，因为在SPTB复杂的妊娠中鉴定胎儿HPA轴的差异基因表达将使我们能够制定新的策略来测试原发性SPTB预防。最终，这种知识有可能告知新型疗法以防止SPTB。