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/摘要在过去的30年中，美国的出生率下降了，而35-55岁的女性出生增加。怀孕的高级遗产年龄更高的妊娠高血压/先兆子痫的风险更高（或2.42）和妊娠糖尿病（或1.11）。长期以来，怀孕一直被认为是一种“压力测试” 愿预告，在易感或已经发展了亚临床病理生理学。需要接受体外受精治疗的老年妇女具有即使在统计上控制年龄，甚至更高的风险也会发展出这些产科并发症。这突出显示可能通过超排除或胚胎引发额外的侮辱文化。不幸的是，医生对为什么是这种情况或如何预测没有机械理解结果更有效。但是，最近的研究检查了积云的转录组谱。细胞以揭示母亲的病理生理。此外，在Young和接受IVF的老年患者。调查结果报告说，女性> 37岁以表达积云细胞的血管生成基因，包括angptl4（牛血管素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- 与胰岛素信号通路相关的36岁过表达基因，例如IGFBP3（胰岛素喜欢生长结合因子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），表明向妊娠相关的糖尿病过渡。我们假设这些基因的过表达，而其他基因的过表达响应了两次打击的物物应力模型，可以预测妊娠糖尿病和高血压的率增加分离率。但是，迄今为止尚无研究遵循纵向的患者，以确定育细细胞是否改变基因表达在临床上相关。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表现。为了解决这个问题，我们提出以下具体目标：特定目标1：将涉及血管生成的候选转录本相关（Angptl4，Lepr，TGFBR3，和FGF2），胰岛素途径（IGFBP3，P1K3R1和IGFBP5），以及带有一般转录物剖面的患有IVF的老年妇女的怀孕并发症；具体目标2：确定多大的在衰老期间，基因表达改变了其积云细胞的基因表达，这些特征可能反映了老化妇女接受IVF。具体目标3：回顾性关联将对AIM 1中的患者进行通过从其积云细胞中获取的分子谱。