Metabolic determinants of early placental development: Acetyl-coA metabolism and histone acetylation during trophoblast differentiation

早期胎盘发育的代谢决定因素：滋养层分化过程中的乙酰辅酶A代谢和组蛋白乙酰化

• 批准号: MR/W027046/1
• 负责人: Irving Aye
• 金额: $ 176.42万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW027046%2F1
• 关键词: Metabolic; determinants; early; placental; development

Major pregnancy disorders originate from poor placental development in the first-trimester of pregnancy. Preeclampsia is a pregnancy-specific complication affecting 6-8% of women and can lead to premature delivery, fetal growth restriction, and increased risk of mortality to mother and child. A poorly functioning placenta caused by impaired placental formation in early pregnancy is implicated in the development of preeclampsia.Placental formation depends on cells called trophoblasts transforming into specialised cell-types. This process is dependent on the coordinated changes in sets of genes. Activation of these genes requires access to DNA regions that is determined by histone proteins that package DNA. Chemical modifications in histones influence their ability to package DNA. Specifically, addition of the molecule acetyl-coA leads to DNA loosening from histones facilitating gene activation. Acetyl-coA is generated from nutrients and used for energy production and histone modifications. I will examine the processes by which acetyl-coA is generated in trophoblasts and how these processes affect cell transformation and placental formation via modification of histone proteins. Moreover, I will investigate if these processes are impaired in preeclampsia and the causes of the impairments. The findings from this study are important for understanding how placental nutrient handling influences placental formation and will help us understand how this process is perturbed in a pregnancy disorder leading to poor outcomes in the mother and the baby.

主要的妊娠障碍源于妊娠前三个月胎盘发育不良。先兆子痫是一种妊娠特异性并发症，影响6-8%的妇女，可导致早产，胎儿生长受限，并增加母亲和儿童死亡的风险。妊娠早期胎盘形成受损导致的胎盘功能低下与先兆子痫的发生有关。胎盘的形成依赖于称为滋养层的细胞转化为专门的细胞类型。这个过程依赖于基因组的协调变化。这些基因的激活需要进入由包装DNA的组蛋白决定的DNA区域。组蛋白中的化学修饰影响其包装DNA的能力。具体来说，乙酰辅酶A分子的加入导致DNA从组蛋白上松动，促进基因激活。乙酰辅酶A由营养素产生，用于能量产生和组蛋白修饰。我将研究乙酰辅酶A在滋养层中产生的过程，以及这些过程如何通过组蛋白的修饰影响细胞转化和胎盘形成。此外，我将调查这些过程是否在先兆子痫中受损以及受损的原因。这项研究的发现对于了解胎盘营养处理如何影响胎盘形成非常重要，并将帮助我们了解这一过程在妊娠障碍中如何受到干扰，从而导致母亲和婴儿的不良结局。

项目成果

Physiologically relevant culture medium Plasmax improves human placental trophoblast stem cell function.

• DOI: 10.1152/ajpcell.00581.2022
• 发表时间: 2023-04-01
• 期刊: American journal of physiology. Cell physiology