Project 3 - Brayboy

项目 3 - Brayboy

• 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
• 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

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 在过去的30年里，美国的出生率一直在下降，而年龄在35-55岁之间的女性的生育率却在下降。 增加高龄孕妇发生妊娠期高血压/先兆子痫的风险更高 (OR妊娠期糖尿病（OR 1.11）。怀孕一直被认为是一种“压力测试”， 可能预示着易患或已经患上显性疾病的老年妇女的发展， 发展出亚临床病理生理学。需要体外受精治疗的老年妇女有一个 即使在统计上控制了年龄，发生这些产科并发症的风险也更高。这 强调了一个额外的伤害可能是由超数排卵或胚胎引起的， 文化不幸的是，医生没有机械的理解，为什么会这样，或如何预测 更有效的结果。然而，最近的研究检查了积云的转录组特征 细胞来揭示母亲的病理生理。此外，卵丘细胞转录组在年轻人和成年人中是不同的。 接受IVF的老年患者。研究结果表明，37岁以上的女性表现出过度表达的 卵丘细胞的血管生成基因，包括ANGPTL 4（血管生成素样4），LEPR（瘦素受体）， TGFBR 3（转化生长因子β受体III）和FGF 2（成纤维细胞生长因子）。即使是31岁的病人- 36岁的人过表达与胰岛素信号通路相关的基因，如IGFBP 3（胰岛素样 生长结合因子3）、P1 K3 R1（磷酸肌醇-3-激酶，调节亚基1（α））和IGFBP 5 （胰岛素样生长因子结合蛋白5），表明过渡到妊娠相关糖尿病。我们 假设这些基因和其他基因过度表达响应于母体压力的两次打击模型， 可以预测老年人中妊娠期糖尿病和高血压的发病率增加， 产妇然而，迄今为止还没有研究对患者进行纵向随访，以确定改变的卵丘细胞是否 基因表达与临床相关。我们的目标是确定这些指标在积云中的有效性 细胞在老年人中预测疾病的表现。为解决这一问题，我们提出以下具体建议： 目的： 具体目标1：将参与血管生成的候选转录物（ANGPTL 4、LEPR、TGFBR 3、 和FGF 2）、胰岛素途径（IGFBP 3、P1 K3 R1和IGFBP 5）以及一般转录物谱的基因表达。 接受IVF的老年妇女的妊娠并发症; 具体目标二： 确定小鼠 在衰老过程中改变了卵丘细胞中的基因表达，以及这些基因表达谱如何反映衰老 接受IVF的女性 具体目标3： 将对目标1中的患者进行回顾性关联 从他们的卵丘细胞中获取的分子图谱。