In-utero Exposure and Infant Loss of IGF2 Imprinting

子宫内暴露和婴儿 IGF2 印记丧失

• 批准号: 7145764
• 负责人: Cathrine Hoyo
• 金额: $ 19.45万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145764
• 关键词: DNA methylation; cell cycle; clinical research; cord blood; embryo /fetus toxicology; environmental exposure; environmental toxicology; epidemiology; epigenetics; gene environment interaction; gene expression; genomic imprinting; human subject; infant human (0-1 year); insulinlike growth factor; molecular pathology; passive smoking; patient oriented research; smoking; tobacco abuse; weight gain

DESCRIPTION (provided by applicant): Loss of Imprinting in IGF2 has been found in a wide spectrum of adult chronic diseases jncluding diabetes, cardiovascular diseases and malignancies. IGF2 imprint disorders have also been reported in patients with the human overgrowth disorder Beckwith-Wiedemann syndrome. Patients with Wilm's tumor and hepatoblastoma have a higher prevalence of LOI in IGF2. Methylation changes of differentially methylated regions on exon 3 and 9 of IGF2 have also been reported in lymphocytes of patients with colon cancer and leukemia. Factors underlying these epigenetic alterations are unknown, although environmental exposures such as cigarette smoking have been implicated. The timing of this epigenetic event is also unknown, although accumulating evidence suggests that LOI in IGF2 may occur in-utero. We hypothesize that LOI in IGF2 is a response, in part, to aberrant methylation changes in IGF2, and because these methylation patterns are mitotically heritable, contributes to deleterious outcomes inherent in IGF2 deregulation. The specific aims of the study are: 1) To characterize methylation patterns and estimate the prevalence of LOI in IGF2 in-utero; 2) To evaluate whether maternal exposure to cigarette smoking is associated with LOI in IGF2; and 3) To evaluate whether LOI in IGF2 is associated with rapid infant weight gain during the first year of life, characteristic of infants of smoking mothers. The proposed research builds on an existing data collection structure of the Cord Blood Transplantation (COBLT) Project. This project recruits and stores cord blood of participants from all Obstetrics Care facilities in Durham, Orange and Wake Counties. We will prospectively identify 200 smoking and 200 non-smoking mothers from the Project database and obtain up to 5ml of cord blood at delivery to determine IGF2 DNA methylation patterns and biallelic expression of IGF2. We will then examine these patterns according to maternal smoking status and infant weight gain. Because LOI is potentially reversible with imprinting restored since the DMA sequence remains unaltered, (unless mutation is in genes regulating methylation) identifying the timing of IGF2 LOI and factors influencing this epigenetic event has wide ranging intervention prospects on clinically apparent chronic disease incidence. The proposed study also has the potential to provide a foundation for future studies investigating the etiology of chronic diseases, including diabetes, cardiovascular diseases and some cancers.

描述（由申请人提供）：在多种成年慢性疾病中发现了IGF2中的印迹丧失，这些疾病会导致糖尿病，心血管疾病和恶性肿瘤。人类过度生长疾病患者Beckwith-Wiedemann综合征也已经报道了IGF2烙印障碍。 Wilm肿瘤和肝母细胞瘤患者在IGF2中患有LOI的患病率更高。在结肠癌和白血病患者的淋巴细胞中，还报道了IGF2外显子3和9差异甲基化区域的甲基化变化。尽管涉及诸如香烟吸烟之类的环境暴露，但这些表观遗传改变的基础是未知的因素。该表观遗传事件的时机也未知，尽管积累的证据表明IGF2中的LOI可能发生在UTERO中。我们假设IGF2中的LOI部分是对IGF2中异常甲基化变化的一种反应，并且由于这些甲基化模式在有丝分裂上是可遗传的，因此有助于IGF2固有的受害结果。该研究的具体目的是：1）表征甲基化模式并估计IGF2 In-Utero中LOI的流行； 2）评估孕妇在IGF2中吸烟是否与LOI有关； 3）评估IGF2中的LOI是否与生命第一年的婴儿体重快速增加有关，这是吸烟母亲的婴儿的特征。拟议的研究建立在脐带血移植（COBLT）项目的现有数据收集结构的基础上。该项目招募和存储来自达勒姆，橙色和韦克县所有妇产科护理设施的参与者的脐带血。我们将前瞻性地从项目数据库中识别出200名吸烟和200名非吸烟母亲，并在输送时获得多达5ml的脐带血，以确定IGF2 DNA甲基化模式和IGF2的双重表达。然后，我们将根据孕产妇的吸烟状况和婴儿体重增加来检查这些模式。因为LOI可能会恢复印迹，因为DMA序列仍未改变，但（除非在调节甲基化的基因中突变）识别IGF2 LOI的时间，并且影响这种表观遗传事件的因素具有广泛的干预前景，从而在临床上明显的慢性疾病发生率上的干预前景。拟议的研究还有可能为未来研究的研究提供基础，以研究慢性疾病的病因，包括糖尿病，心血管疾病和一些癌症。