Investigating a novel molecular diagnostic tool for identification and stratification of pregnancy complications

研究一种用于妊娠并发症识别和分层的新型分子诊断工具

• 批准号: MR/R022836/1
• 负责人: Marika Charalambous
• 金额: $ 69.6万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR022836%2F1
• 关键词: Investigating; novel; molecular; diagnostic; tool

Babies who grow poorly in the womb, called small for gestational age (SGA), are at increased risk of health problems for both mother and baby. For example, full-term infants who are SGA have up to 30 times higher risk of neonatal death compared to term infants born at average weight. Screening pregnant women in an attempt to detect SGA babies has the potential to reduce the number of these adverse outcomes -the combined deaths from stillbirth and neonatal problems exceed 5000 babies every year in the UK. Currently it is difficult to monitor growth of the baby in the womb, and even harder to predict if there will be health problems associated with this. While there are a number of scan and blood markers for SGA babies, none of these is good enough on its own to predict them. We have recently found that by measuring a protein called DLK1 in the mother's blood we can improve the prediction of whether the baby will be small. In this first study we examined only a small selection of pregnant women, but the data suggested that abnormal DLK1 levels were associated with failure to make an efficient placenta. The placenta is a temporary organ that is necessary for providing nutrition and oxygen to the baby from the mother's blood, and for removing waste. Many of the complications of pregnancy are thought to occur because the placenta does not develop properly. However, we still have much to discover about which genes are needed to make a healthy placenta, and how this goes wrong if the genes are mutated. Interestingly, DLK1 is made in the placenta. When we studied mice with a mutated DLK1 gene we found that they had smaller placentas and a reduced area for nutrient and oxygen exchange between the maternal and fetal blood. However, we currently don't understand why DLK1 is required to make a healthy placenta. The aim of this project is firstly to see how measuring DLK1 in the blood of a large number of pregnant women can help us improve prediction of small babies. We have access to scan information, blood samples and placental samples from a large scale study of unselected women in their first pregnancy (~3000 women). The overarching aim of the present application is to see if we can find better markers in the mother's blood of poorly grown babies, and further link the levels of DLK1 to problems with the placenta. Secondly, because we have mice without a working DLK1 gene, we can study them to understand the processes necessary to make a healthy placenta. We will use the new ideas generated by studying the mice to design experiments using the human placental samples to test if our findings can help to understand why placentation goes wrong in humans.

在子宫内发育不良的婴儿，称为小于胎龄儿（SGA），母亲和婴儿的健康问题风险增加。例如，与平均体重出生的足月婴儿相比，SGA足月婴儿的新生儿死亡风险高出30倍。筛查孕妇以检测SGA婴儿有可能减少这些不良后果的数量-在英国，死产和新生儿问题的死亡人数每年超过5000名婴儿。目前，很难监测胎儿在子宫内的生长情况，更难预测是否会出现与此相关的健康问题。虽然有一些扫描和血液标记物的SGA婴儿，没有一个是足够好的本身来预测他们。我们最近发现，通过测量母亲血液中一种名为DLK 1的蛋白质，我们可以更好地预测婴儿是否会很小。在第一项研究中，我们只检查了一小部分孕妇，但数据表明，异常的DLK 1水平与无法形成有效的胎盘有关。胎盘是一个临时器官，它是从母亲的血液中为婴儿提供营养和氧气以及清除废物所必需的。许多妊娠并发症被认为是因为胎盘没有正常发育而发生的。然而，我们仍然有很多东西要发现，哪些基因是制造健康胎盘所必需的，以及如果基因发生突变，这是如何出错的。有趣的是，DLK 1是在胎盘中产生的。当我们研究DLK 1基因突变的小鼠时，我们发现它们的胎盘较小，母体和胎儿血液之间的营养和氧气交换面积减少。然而，我们目前还不明白为什么DLK 1需要制造健康的胎盘。该项目的目的是首先了解测量大量孕妇血液中的DLK 1如何帮助我们提高对小婴儿的预测。我们可以从一项针对首次怀孕的女性（约3000名女性）的大规模研究中获得扫描信息、血液样本和胎盘样本。本申请的首要目的是看看我们是否可以在生长不良婴儿的母亲血液中找到更好的标记物，并进一步将DLK 1的水平与胎盘问题联系起来。其次，因为我们有没有DLK 1基因的小鼠，我们可以研究它们，以了解制造健康胎盘所需的过程。我们将利用研究小鼠产生的新想法来设计使用人类胎盘样本的实验，以测试我们的发现是否有助于理解人类胎盘发生错误的原因。

项目成果

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland.

• DOI: 10.3390/genes12040509
• 发表时间: 2021-03-30
• 期刊: Genes
• 影响因子: 3.5
• 作者: Scagliotti V;Costa Fernandes Esse R;Willis TL;Howard M;Carrus I;Lodge E;Andoniadou CL;Charalambous M
• 通讯作者: Charalambous M

A pipeline for making 31 P NMR accessible for small- and large-scale lipidomics studies

使 31 P NMR 可用于小规模和大规模脂质组学研究的管道

• DOI: 10.17863/cam.73457
• 发表时间: 2021
• 作者: Furse S

Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets.

• DOI: 10.1016/j.cmet.2018.02.007
• 发表时间: 2018-03-06
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Macdougall CE;Wood EG;Loschko J;Scagliotti V;Cassidy FC;Robinson ME;Feldhahn N;Castellano L;Voisin MB;Marelli-Berg F;Gaston-Massuet C;Charalambous M;Longhi MP
• 通讯作者: Longhi MP

MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation.

• DOI: 10.1096/fj.201701274rr
• 发表时间: 2018-06-07
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Novoselova TV;Hussain M;King PJ;Guasti L;Metherell LA;Charalambous M;Clark AJL;Chan LF
• 通讯作者: Chan LF

Dlk1 dosage regulates hippocampal neurogenesis and cognition.

• DOI: 10.1073/pnas.2015505118
• 发表时间: 2021-03-16
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Montalbán-Loro R;Lassi G;Lozano-Ureña A;Perez-Villalba A;Jiménez-Villalba E;Charalambous M;Vallortigara G;Horner AE;Saksida LM;Bussey TJ;Trejo JL;Tucci V;Ferguson-Smith AC;Ferrón SR
• 通讯作者: Ferrón SR