Development of endometrial/myometrial organoids to study disorders of pregnancy and parturition

开发子宫内膜/子宫肌层类器官来研究妊娠和分娩疾病

• 批准号: NC/X001075/1
• 负责人: Andrew Blanks
• 金额: $ 59.88万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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=NC%2FX001075%2F1
• 关键词: Development; endometrial; myometrial; organoids; study

Approximately 15% of all clinically recognised pregnancies end in miscarriage, mostly before 12 weeks of gestation. Apart from physical trauma (pain, bleeding, and infection), each miscarriage compounds the risk of significant psychological morbidity (depression, post-traumatic stress disorder, and suicide) and obstetrical complications in a future ongoing pregnancy, foremost preterm birth. Globally, preterm birth, defined as delivery of a baby before 37 completed weeks' gestation, affects 5-18% of live births, although the incidence varies dependent on ethnicity and socioeconomic factors. Preterm birth is the single most important cause of neonatal morbidity and mortality, especially in "very preterm" infants (those born before 32 weeks' gestation). To date, there are no effective preventative treatments for either miscarriage or preterm birth. Clinical management is largely confined to progesterone, a hormone discovered > 90 years ago, but its effectiveness remains contentious. These important reproductive disorders, together with others, remain unresolved largely as a consequence of scientific animal models failing to accurately represent human specific traits. Although animal models, such as mice, are widely used, they do not approximate human pregnancy, nor have they yielded sufficient mechanistic insights to impact demonstrably on clinical practice. Most model organisms such as the mouse, rat and guinea pig, have fundamentally different reproductive strategies when compared to humans, as well as anatomically distinct uteri. Primates, and more specifically Old-World monkeys, are an exception but these models are expensive, ethically contentious, and require specialised facilities. To address the knowledge gap in human uterine diseases, we recently established endometrial assembloids, consisting of lab assembled cultures that contain the main cells of the lining of the uterus.These assembloids can be manipulated to mimic different pathological states associated with reproductive failure, exemplified by co-culturing with human research embryos. This model does not yet contain the main muscle of the uterus the myometrium. Human embryo implantation is deep and involves disruption of the inner myometrial layer, also termed the junctional zone (JZ). Studies have demonstrated that the JZ is important for implantation and fertility and that it is a crucial component of the uterine response to pregnancy. The aim of this proposal is to improve our assembloid model further by the addition of this muscle layer to create a new model of human pregnancy. In doing so we should be able to replace animal experiments by offering a scientifically superior model when considering studies in early human pregnancy and associated diseases. We will also create a new, annual virtual conference, for scientific groups around the world currently attempting to replace animal experiments by using organoid technologies. We will exchange valuable state-of-the-art methods as this productive area of research makes advances and document these methods in a form that can be readily used by researchers interested in adopting these techniques. We already have agreement from over ten of the worlds leading groups to participate in this initiative and we will endeavour to recruit further groups as the conferences become more established.

大约15%的临床认可的妊娠以流产告终，大多数在妊娠12周之前。除了身体创伤（疼痛、出血和感染），每次流产都会增加重大心理疾病（抑郁、创伤后应激障碍和自杀）的风险，并增加未来继续妊娠的产科并发症，最重要的是早产。在全球范围内，早产（定义为在妊娠37周之前分娩婴儿）影响5-18%的活产婴儿，尽管发病率因种族和社会经济因素而异。早产是新生儿发病率和死亡率的唯一最重要原因，特别是在“极早产”婴儿（妊娠32周之前出生的婴儿）中。到目前为止，还没有有效的预防流产或早产的治疗方法。临床管理主要局限于孕激素，一种90多年前发现的激素，但其有效性仍然存在争议。这些重要的生殖疾病，以及其他疾病，仍然没有得到解决，主要是由于科学的动物模型未能准确地代表人类的具体特征。虽然动物模型，如小鼠，被广泛使用，但它们并不接近人类妊娠，也没有产生足够的机制见解，以影响临床实践。大多数模式生物，如小鼠、大鼠和豚鼠，与人类相比，具有根本不同的生殖策略，以及解剖学上不同的子宫。灵长类动物，更具体地说是旧世界的猴子，是一个例外，但这些模型是昂贵的，道德上有争议的，需要专门的设施。为了填补人类子宫疾病的知识空白，我们最近建立了子宫内膜类胚体，由实验室组装的培养物组成，其中含有子宫内膜的主要细胞。这些类胚体可以被操纵来模拟与生殖失败相关的不同病理状态，例如与人类研究胚胎共培养。这个模型还不包含子宫的主要肌肉--子宫肌层.人类胚胎植入是深的，涉及子宫肌层内层的破坏，也称为结合区（JZ）。研究表明，JZ对着床和生育力很重要，是子宫对妊娠反应的重要组成部分。这项提议的目的是通过增加这一肌肉层来进一步改善我们的拟人模型，以创造一种新的人类妊娠模型。这样，我们就可以在考虑人类早期妊娠和相关疾病的研究时，通过提供一个科学上更优越的上级模型来取代动物实验。我们还将创建一个新的年度虚拟会议，为世界各地目前试图通过使用类器官技术取代动物实验的科学团体提供服务。我们将交流有价值的最先进的方法，因为这一富有成效的研究领域取得了进展，并以一种易于被有兴趣采用这些技术的研究人员使用的形式记录这些方法。我们已经得到世界上10多个主要团体的同意，参加这一倡议，随着会议的进一步建立，我们将努力吸收更多的团体参加。