Project 3 - Brayboy

项目 3 - Brayboy

基本信息

批准号：
9883807
负责人：
LYNAE M BRAYBOY
金额：
$ 2.32万
依托单位：
WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883807
关键词：
ANGPTL4 gene Address Age Age-Years Aging Area Assisted Reproductive Technology Attention Binding Biological Markers Birth Birth Rate Birth Weight Candidate Disease Gene Cells Centers of Research Excellence Chronic Clinical Data Databases Development Diabetes Mellitus Diagnosis Disease Environment FGF2 gene Fertilization in Vitro Fibroblast Growth Factor First Pregnancy Trimester Functional disorder Future Gene Expression Genes Gestational Age Gestational Diabetes Growth Human IGFBP3 gene IGFBP5 gene Insulin Insulin Signaling Pathway Insulin-Like Growth Factor Binding Protein 5 LEPR gene Life Cycle Stages Modeling Molecular Molecular Profiling Mothers Mus Neonatal Oocytes Ovarian Follicle Pathway interactions Patients Phosphatidylinositols Phosphotransferases Physicians Postpartum Period Pre-Eclampsia Prealbumin Predisposition Pregnancy Pregnancy Complications Pregnancy Outcome Pregnancy Rate Preventive care Prospective Studies Regulatory T-Lymphocyte Reporting Reproductive Health Severities Societies Stress Stress Tests Superovulation TGF beta type III receptor TGFBR3 gene Testing Transcript Woman Work advanced maternal age aged angiogenesis clinically relevant design diminished ovarian reserve electronic data embryo culture experience fetal high risk leptin receptor maternal outcome maternal stress neonatal outcome obstetrical complication older women outcome prediction overexpression peripheral blood pregnancy hypertension prenatal testing programmed cell death protein 1 prospective reproductive reproductive senescence response screening transcriptome transcriptomics

项目摘要

ABSTRACT/SUMMARY The US birth rate has fallen over the past 30 years while births from women ages 35-55 instead have increased. Advanced maternal age in pregnancy carries a higher risk of gestational hypertension/preeclampsia (OR 2.42), and gestational diabetes (OR 1.11). Pregnancy has long been regarded as a “stress test” which may herald the development of overt diseases in older women who are predisposed, or have already developed subclinical pathophysiology. Older women who require treatment with in vitro fertilization have an even higher risk of developing these obstetric complications even when controlling statistically for age. This highlights that an additional insult may be initiated by superovulation or perhaps embryo culture. Unfortunately, physicians have no mechanistic understanding of why this is the case, or how to predict the outcome more effectively. However, recent studies have examined the transcriptomic profile of cumulus cells to reveal pathophysiology in the mother. Further, the cumulus cell transcriptome is different in young and aged patients undergoing IVF. The findings report that women >37 years old showed over expression of angiogenic genes by the cumulus cells, including ANGPTL4 (angiopoietin like 4), LEPR (leptin receptor), TGFBR3 (transforming growth factor beta receptor III), and FGF2 (fibroblast growth factor). Even patients 31- 36 years of age overexpressed genes related to the insulin signaling pathway such as IGFBP3 (insulin like growth binding factor 3), P1K3R1 (Phosphoinositide-3-Kinase, Regulatory Subunit 1 (Alpha)), and IGFBP5 (Insulin-Like Growth Factor Binding Protein 5), suggesting a transition to pregnancy-related diabetes. We hypothesize that overexpression of these genes and others responsive to a two-hit model of maternal stress, could be predictive for the increased rates of gestational diabetes and hypertension manifested in older parturients. However, no study to date has followed patients longitudinally to determine if altered cumulus cell gene expression is clinically relevant. Our objective is to determine how effective these metrics in the cumulus cells are in aged humans in predicting disease manifestation. To address this we propose the following specific aims: Specific Aim 1: Correlate candidate transcripts involved in angiogenesis (ANGPTL4, LEPR, TGFBR3, and FGF2), of the insulin pathway (IGFBP3, P1K3R1 and IGFBP5), and of general transcript profiles with pregnancy complications in aged women undergoing IVF; Specific Aim 2: Determine how significantly mice have altered gene expression in their cumulus cells during aging and how these profiles may reflect aged women undergoing IVF. Specific Aim 3: Retrospective associations will be conducted on patients in Aim 1 with the molecular profiles acquired from their cumulus cells.

摘要/总结过去 30 年来，美国的出生率有所下降，而 35 至 55 岁女性的出生率却下降了高龄孕妇患妊娠期高血压/先兆子痫的风险更高。（OR 2.42）和妊娠糖尿病（OR 1.11）长期以来一直被视为一种“压力测试”。可能预示着有倾向或已经患有明显疾病的老年妇女的发展需要体外受精治疗的老年女性具有亚临床病理生理学特征。即使控制研究人员的年龄，发生这些产科并发症的风险甚至更高。强调额外的损伤可能是由超排卵或胚胎引起的不幸的是，医生对为什么会出现这种情况或如何预测没有机械性的理解。然而，最近的研究检查了积云的转录组学特征。细胞揭示母亲的病理生理学此外，年轻和年轻的卵丘细胞转录组是不同的。接受 IVF 的老年患者的研究结果表明，>37 岁的女性表现出过度表达。卵丘细胞的血管生成基因，包括 ANGPTL4（血管生成素样 4）、LEPR（瘦素受体）、 TGFBR3（转化生长因子β受体III）和FGF2（成纤维细胞生长因子）甚至患者31-。 36岁过度表达胰岛素信号通路相关基因，如IGFBP3（胰岛素样生长结合因子 3)、P1K3R1（磷酸肌醇 3-激酶、调节亚基 1 (Alpha)）和 IGFBP5 （胰岛素样生长因子结合蛋白 5），表明向妊娠相关糖尿病的转变。特别是这些基因和其他基因的过度表达对母体压力的两次打击模型有反应，可以预测老年人妊娠期糖尿病和高血压的发病率增加然而，迄今为止还没有研究纵向跟踪患者以确定卵丘细胞是否存在。基因表达具有临床相关性，我们的目标是确定这些指标在积云中的有效性。为了解决这个问题，我们提出了以下具体建议。目标：具体目标 1：关联参与血管生成的候选转录本（ANGPTL4、LEPR、TGFBR3、和 FGF2）、胰岛素途径（IGFBP3、P1K3R1 和 IGFBP5）以及一般转录谱接受体外受精的老年妇女的妊娠并发症；具体目标2：确定小鼠的显着程度在衰老过程中卵丘细胞中的基因表达发生了变化，以及这些特征如何反映衰老接受体外受精的女性。具体目标 3：将对目标 1 中的患者进行回顾性关联从卵丘细胞获得的分子谱。