Organoid systems to identify endometrial origins of pre-eclampsia

识别先兆子痫子宫内膜起源的类器官系统

• 批准号: MR/X021289/1
• 负责人: Peter Ruane
• 金额: $ 82.35万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021289%2F1
• 关键词: Organoid; systems; identify; endometrial; origins

Diseases of pregnancy can have serious affects on both mother and baby's health, and even in mild cases can overshadow what is supposed to be one of life's most joyous events. Pre-eclampsia (PE) is a common disease occurring in up to 5% of all pregnancies and it can have both severe and more mild forms. PE is most serious when it manifests before 34 weeks of pregnancy, and although this early-onset type of the disease is the most well studied we still do not understand what the root cause is. We do know that it is the placenta not functioning properly that causes the dangerous high blood pressure and kidney symptoms characteristic of PE, but the only way we know how to stop progression of the disease is to deliver the baby, often before it is ready. If we understand why the placenta malfunctions in PE then we may be able to design better treatments and even recognise those at risk of disease before it develops.This project aims to reconstruct the formation of key parts of the placenta and ask the question whether it is the mother's womb that initiates a chain of events leading to placental malfunction in PE. The placenta develops alongside the baby during pregnancy, acting as the go-between for nutrient and waste handling to allow baby to grow. It begins to form right as the fertilised egg implants into the womb and builds structures called placental villi that invade deep into the womb lining to access arterial blood as the nutrient source for baby's growth. It is this placental interface with maternal arteries that doesn't form properly in early-onset PE, leading to poor growth for the baby and imbalances in the mother's cardiovascular system that can eventually lead to life-threatening symptoms. A series of independent studies over the last decade detected subtle abnormalities in the womb tissue of mothers with PE or those that have had it recurrently. These mostly observational studies suggest that in early-onset PE the womb doesn't properly prepare for pregnancy prior to and after fertilisation; a process called decidualisation. Recent advances in our understanding of how cells work together to form tissues and organs has led us to be able to grow whole pieces of womb and placental tissue in the lab. Investigating how these placental and womb 'organoids' develop together will help us identify for the first time how the womb triggers malformation of the placenta in early-onset PE. At our clinical research centre in Manchester, sufferers of recurrent early-onset PE have graciously consented to womb biopsies outside of pregnancy. Womb cells and organoids can be developed from these biopsies and re-combined to configure a 'decidual niche' in a petri dish. Placental organoids formed from standardised cells can then be developed within this PE decidual niche and compared to organoids developed in a decidual niche made with biopsies from women who have had healthy pregnancies. This comparison will take the form of extremely high resolution analysis of the organoids using a technique called single cell transcriptomics; essentially characterising each cell in the organoid based on the genes they express and so defining different cell types and their relationships with one another. Placental organoids contain the cell types that invade and access womb arteries and so the effects of the PE decidual niche on these crucial cells will be detected by single cell transcriptomics. Validation of the effects of PE decidua relative to actual PE disease state can be made through comparison to transcriptomes from of more than 150 PE placentas. Moreover, the single cell transcriptome approach combined with computational modelling will allow the identification of the exact signals from PE decidua that drive placental malformation. Understanding this will inform future drug targeting for treatment and may lead to detection of those at risk of developing PE before pregnancy.

妊娠期疾病会对母亲和婴儿的健康产生严重影响，即使在轻微的情况下，也会使本应是生活中最快乐的事件之一蒙上阴影。先兆子痫（PE）是一种常见的疾病，发生在高达5%的所有怀孕，它可以有严重和更温和的形式。PE在怀孕34周之前表现出来时最严重，尽管这种早发性疾病是研究最充分的，但我们仍然不知道根本原因是什么。我们确实知道，胎盘功能不正常会导致危险的高血压和PE特有的肾脏症状，但我们知道如何阻止疾病进展的唯一方法是分娩婴儿，通常在婴儿准备好之前。如果我们理解了PE中胎盘功能障碍的原因，那么我们就可以设计出更好的治疗方法，甚至在疾病发生之前就能识别出那些有患病风险的人。该项目旨在重建胎盘关键部位的形成，并提出一个问题，即是否是母亲的子宫引发了导致PE中胎盘功能障碍的一系列事件。胎盘在怀孕期间与婴儿一起发育，作为营养和废物处理的中间人，让婴儿成长。当受精卵植入子宫时，它就开始形成，并建立称为胎盘绒毛的结构，这些绒毛侵入子宫内膜深处，进入动脉血，作为婴儿生长的营养来源。正是这种胎盘与母体动脉的界面在早发性PE中不能正常形成，导致婴儿生长不良和母亲心血管系统失衡，最终可能导致危及生命的症状。在过去的十年里，一系列独立的研究发现了患有PE或复发性PE的母亲子宫组织的细微异常。这些主要是观察性研究表明，在早发性PE中，子宫在受精前后没有为怀孕做好适当的准备;这一过程称为蜕膜化。最近，我们对细胞如何共同形成组织和器官的理解取得了进展，使我们能够在实验室中培养完整的子宫和胎盘组织。研究这些胎盘和子宫“类器官”如何共同发育将有助于我们首次确定子宫如何触发早发性PE中的胎盘畸形。在我们位于曼彻斯特的临床研究中心，复发性早发性肺栓塞的患者已经欣然同意在妊娠期外进行子宫活检。子宫细胞和类器官可以从这些活检中发育出来，并在培养皿中重新组合以形成“蜕膜生态位”。然后，由标准化细胞形成的胎盘类器官可以在这个PE蜕膜龛内发育，并与在用健康怀孕的妇女的活检制成的蜕膜龛中发育的类器官进行比较。这种比较将采用一种称为单细胞转录组学的技术对类器官进行极高分辨率的分析;基本上是根据它们表达的基因来表征类器官中的每个细胞，从而定义不同的细胞类型及其相互关系。胎盘类器官含有侵入和进入子宫动脉的细胞类型，因此PE蜕膜生态位对这些关键细胞的影响将通过单细胞转录组学检测。PE蜕膜相对于实际PE疾病状态的作用的验证可以通过与来自超过150个PE胎盘的转录组进行比较来进行。此外，单细胞转录组方法与计算建模相结合将允许识别来自PE蜕膜的驱动胎盘畸形的确切信号。了解这一点将为未来的药物靶向治疗提供信息，并可能导致在怀孕前发现有发生PE风险的人。