Ensuring quality maternal care in an adverse environment

在不利的环境下确保优质的孕产妇护理

• 批准号: BB/P002307/1
• 负责人: Rosalind John
• 金额: $ 64.37万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP002307%2F1
• 关键词: Ensuring; quality; maternal; care; adverse

A critically important adaptation during the mammalian pregnancy is the induction of maternal care. Maternal care is vitally important for the survival of the newborn and the withdrawal of maternal care or poor quality maternal care can result in adverse behavioural and metabolic outcomes later in life. Importantly, prenatal adversities such as suboptimal diet or stress can influence the quality of maternal care. Consequently, understanding how maternal care is induced and how the maternal environment influences the induction of maternal care is of paramount importance.There is some evidence that the placenta plays a role in instructing the mother to care for her newborns. The placenta is a transient organ of pregnancy that plays a key role in transferring nutrients to the growing fetus. The placenta is also a super endocrine organ that manufactures hormones that flood the maternal system to induce the changes required for a successful, health pregnancy. Studies suggest that some of these hormones, the placental lactogens, may induce maternal care. Given this proposed role for the placenta, placental dysfunction could contribute to poor maternal care. We have identified a gene called Phlda2 that is important for the production of these placental hormones. Phlda2 regulates the amount of placental hormones that are manufactured by regulating the size of the placental endocrine compartment. Transgenic over expression of Phlda2 results in a smaller endocrine compartment. Mouse mothers exposed to placenta with this much smaller endocrine compartment exhibit changes in gene expression and neurogenesis in the maternal brain during pregnancy and poor maternal care of their offspring, even though they themselves are not mutant for Phlda2. Phlda2 is an imprinted gene whose expression is regulated by epigenetic marks. Remarkably, expression of Phlda2 is altered in the placenta in response to the two different suboptimal maternal diets that have previously been linked to poor maternal care. This leads us to believe that a suboptimal maternal diet may contribute to poor maternal care by altering the expression of Phlda2 in the placenta and thus reducing exposure of the maternal brain to placental lactogens. In this study, we will use a variety of existing experimental models and techniques to test this hypothesis first asking whether we can restore maternal care by manipulating placental expression of Phlda2 in a dietary model, and then by exploring the mechanism initially focusing on placental lactogen signaling via the maternal prolactin receptor. We will also develop a novel imaging tool based on infrared luciferase, to ask whether we can longitudinally bioimage ongoing maternal neurogenesis. A considerable advantage of this tool will be the ability to image the same animal multiple times substantially reducing the number of animals required for our studies.This work is important not just in helping us to fundamentally understand how maternal care is induced but also how this process may be influenced by the maternal environment, and how we might be able to restore maternal care - work that will have wide relevance to the welfare of experimental, domestic and agricultural animals as well as human health.

哺乳动物怀孕期间一个至关重要的适应是母性照顾的诱导。孕产妇保健对新生儿的生存至关重要，停止孕产妇保健或质量差的孕产妇保健可导致生命后期的不良行为和代谢结果。重要的是，产前逆境，如不理想的饮食或压力可以影响产妇护理的质量。因此，了解产妇护理是如何诱导的，以及产妇环境如何影响产妇护理的诱导是至关重要的。有证据表明，胎盘在指导母亲照顾新生儿方面发挥了作用。胎盘是妊娠的一个短暂器官，在向生长中的胎儿输送营养方面起着关键作用。胎盘也是一个超级内分泌器官，它产生的激素充斥着母体系统，诱导成功、健康怀孕所需的变化。研究表明，其中一些激素，即胎盘乳原，可能会引起产妇护理。考虑到胎盘的这一作用，胎盘功能障碍可能导致产妇护理不良。我们已经确定了一种叫做Phlda2的基因，它对胎盘激素的产生很重要。Phlda2通过调节胎盘内分泌室的大小来调节胎盘激素的分泌量。Phlda2转基因过表达导致更小的内分泌室。暴露在具有这种小得多的内分泌室的胎盘中的小鼠母亲在怀孕期间表现出基因表达和母脑神经发生的变化，并且母亲对其后代的照顾较差，即使它们本身不是Phlda2突变体。Phlda2是一种印迹基因，其表达受表观遗传标记调控。值得注意的是，Phlda2的表达在胎盘中发生改变，以响应两种不同的次优母体饮食，这两种饮食先前被认为与母体护理不良有关。这使我们相信，不理想的母体饮食可能通过改变胎盘中Phlda2的表达，从而减少母体大脑对胎盘乳原的暴露，从而导致母体护理不良。在本研究中，我们将使用各种现有的实验模型和技术来验证这一假设，首先询问我们是否可以通过在饮食模型中操纵胎盘Phlda2的表达来恢复母体的护理，然后探索其机制，初步关注胎盘乳素信号通过母体催乳素受体传导。我们还将开发一种基于红外荧光素酶的新型成像工具，以询问我们是否可以对正在进行的母体神经发生进行纵向生物成像。该工具的一个相当大的优势是能够对同一动物进行多次成像，大大减少了我们研究所需的动物数量。这项工作的重要性不仅在于帮助我们从根本上了解产妇护理是如何产生的，而且还在于了解这一过程如何受到产妇环境的影响，以及我们如何能够恢复产妇护理——这项工作将与实验动物、家畜和农业动物的福利以及人类健康有着广泛的相关性。

项目成果

In support of the placental programming hypothesis: Placental endocrine insufficiency programs atypical behaviour in mothers and their offspring.

• DOI: 10.1113/ep089916
• 发表时间: 2022-05
• 期刊: EXPERIMENTAL PHYSIOLOGY
• 影响因子: 2.7
• 作者: John, Rosalind M.

Maternal care boosted by paternal imprinting in mammals.

哺乳动物的父系印记促进了母性护理。

• DOI: 10.1371/journal.pbio.2006599
• 发表时间: 2018-07
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Creeth HDJ;McNamara GI;Tunster SJ;Boque-Sastre R;Allen B;Sumption L;Eddy JB;Isles AR;John RM
• 通讯作者: John RM

Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring.

• DOI: 10.1093/hmg/ddab154
• 发表时间: 2021-09-15
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Harrison DJ;Creeth HDJ;Tyson HR;Boque-Sastre R;Hunter S;Dwyer DM;Isles AR;John RM
• 通讯作者: John RM

The placental programming hypothesis: Placental endocrine insufficiency and the co-occurrence of low birth weight and maternal mood disorders

• DOI: 10.1016/j.placenta.2020.03.011
• 发表时间: 2020-09-01
• 期刊: PLACENTA
• 影响因子: 3.8
• 作者: Creeth, H. D. J.;John, R. M.
• 通讯作者: John, R. M.