A LONGITUDINAL STUDY OF LOSS OF IMPRINTING IN FIRST TRIMESTER CVS SAMPLES COMPARE

妊娠早期 CVS 样本印记损失的纵向研究比较

• 批准号: 8828969
• 负责人: Men-Jean Lee
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-25 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828969
• 关键词: LONGITUDINAL; STUDY; LOSS; IMPRINTING; FIRST

Principal Investigator/Program Director (Last, first, middle): Lee, Men-Jean Project Summary For most human genes, maternal and paternal alleles are bi-allelically expressed. However, a specific subset of genes are imprinted and mono-allelically expressed. The current dogma is that this embryonic imprint is stable across the lifespan of the organism. Loss of imprinting (LOI) leads to bi-allelic expression of the imprinted gene, potentially causing a doubling of gene dosage or gene dysregulation, resulting in disease. Because the methylation marks of imprinted genes are considered permanent after fertilization, any acquired changes in the intrauterine environment may lead to stable transgenerational effects. The regulatory complexity of these imprinted gene domains may render them particularly sensitive to environmental changes such as diet and nutrition. Emerging evidence implicates aberrant imprinting in the pathophysiology of many common human diseases, including complications of pregnancy such as intrauterine growth restriction (IUGR) and preeclampsia (PE); and even postnatal disorders such as obesity, cardiovascular disease, and type 2 diabetes. We have developed a highly sensitive and quantitative allele-specific PCR analysis to measure LOI in a panel of imprinted genes in the human genome. Using this methodology, we have already determined that pregnancies complicated by PE and IUGR are associated with dysregulation of a set of imprinted genes in the placenta. Both of these obstetrical disorders have their origins in an early intrauterine environment associated with aberrant placentation and trophoblast invasion. We also have novel evidence to suggest that genomic imprinting patterns are not permanently fixed in placental development. Contrary to the prevailing theory, we hypothesize that patterns of LOI are not static in the human placenta and are subject to developmental and environmental influences over the course of pregnancy that predispose to adverse pregnancy outcome. We now propose a longitudinal trial as a secondary study to the NuMOM2B Trial to monitor LOI in placenta samples from first trimester CVS to birth and determine which LOI patterns in the first trimester lead to normal pregnancy outcomes and which patterns are predictive of pregnancy complications. Project Description Page 7

主要研究者/项目负责人（最后，第一，中间）：Lee，Men-Jean 项目摘要 对于大多数人类基因，母本和父本等位基因是双等位基因表达的。然而，一个特定的子集 基因的印记和单等位基因表达。目前的教条是，这种胚胎印记是 在生物体的整个生命周期内保持稳定。印迹缺失（LOI）导致了DNA的双等位基因表达。 印迹基因，可能导致基因剂量加倍或基因失调，导致疾病。 由于印迹基因的甲基化标记在受精后被认为是永久性的， 子宫内环境的变化可能导致稳定的跨代效应。监管 这些印记基因结构域的复杂性可能使它们对环境变化特别敏感 例如饮食和营养。新出现的证据表明，在许多疾病的病理生理学中， 常见的人类疾病，包括妊娠并发症，如宫内生长受限（IUGR） 和先兆子痫（PE）;甚至产后疾病，如肥胖，心血管疾病，2型糖尿病， 糖尿病我们已经开发了一种高灵敏度和定量等位基因特异性PCR分析来测量LOI 在人类基因组的一组印记基因中。使用这种方法，我们已经确定 妊娠合并PE和IUGR与一组印记基因的失调有关， 胎盘这两种产科疾病都起源于早期子宫内环境， 异常胎盘形成和滋养层侵入我们也有新的证据表明， 印记模式在胎盘发育中不是永久固定的。与流行的理论相反， 我们假设LOI的模式在人类胎盘中不是静态的， 在怀孕过程中的环境影响，易患不良妊娠结局。我们 现在提出一项纵向试验作为NuMOM 2B试验的次要研究，以监测胎盘中的LOI 从第一个三个月的CVS到出生的样本，并确定第一个三个月的LOI模式导致正常 妊娠结局以及哪些模式可预测妊娠并发症。 项目描述第7页