Maternal mechanisms induced by diet regulating embryo developmental plasticity affecting life-long health

成人心血管和代谢疾病的流行率在全世界继续以流行病的速度增加。对病人的研究表明，这类疾病的风险因素与产前生活条件的关系更密切，如产妇营养的质量，而不是当代生活方式因素。我们的工作，使用啮齿动物模型，已经证明，胚胎发育的最早阶段，在植入发生之前，对母体营养水平高度敏感。此时母体蛋白质营养不良可能会改变胚胎的发育方式，试图提高其生存机会并称为“发育可塑性”，但最终导致成年后心血管和代谢疾病的风险增加。关于试管婴儿儿童的新数据显示，他们在培养胚胎时也会经历相对较差的营养条件，血压升高和代谢紊乱的风险增加。最近，我们的研究集中在胚胎对母亲不良饮食的反应机制，以及这些反应如何改变随后的发育计划和成人健康，然而，我们仍然不知道这些反应是如何首先激活的。如果我们能发现是什么确切地诱导胚胎的发育可塑性，这些信息将使我们能够设计出预防不良健康后果的策略。我们有大量的初步数据表明，母亲利用子宫腔内的氨基酸和可能的胰岛素的组成来向胚胎传达营养水平差的信息，然后激发胚胎的发育可塑性以提高存活率，但导致成年疾病。我们将使用我们开发的胚胎体外培养模型来模拟子宫腔内的条件，以调节这种通信途径，并精确确定引起胚胎反应的氨基酸和胰岛素的分子构型。这些反应和影响以后的发展和成人疾病的风险将密切监测胚胎移植到养母。这些信息将使我们能够以精确的方式补充产妇的饮食，试图阻止不利的发展规划影响成人健康。我们研究的第二部分涉及母亲对不良饮食的反应的进一步机制。我们的初步数据表明，子宫壁被诱导产生增加的血管供应，以响应植入时的不良饮食。这一发现提出了一个新的概念，即母亲可以在妊娠早期响应于不良饮食而增强营养传递，补充由胚胎反应介导的活动。这种母体反应将被充分表征并评估它是对母体内饮食信号的直接反应还是代表胚胎介导的信号的结果。我们还将定量评估子宫血管化增强对胚胎和胎儿存活和生长的贡献，相对于胚胎发育可塑性的其他方面。这些与发育规划相关的母体机制的研究将为进一步制定饮食/药理学策略以对抗不良妊娠诱导疾病提供强大的资源。

The prevalence of adult cardiovascular and metabolic diseases continues to increase worldwide at an epidemic rate. Studies on patients have shown that risk factors for such diseases relate more strongly to conditions of prenatal life, such as the quality of maternal nutrition, that contemporary lifestyle factors. Our work, using rodent models, has demonstrated that the earliest stage of embryo development, before implantation has occurred, is highly sensitive to maternal nutrient levels. Poor maternal protein nutrition at this time can change how the embryo develops, an attempt to heighten its survival chances and called 'developmental plasticity', but which ultimately leads to increased risk of cardiovascular and metabolic disease in later adult life. New data on IVF children who would also have experienced relatively poor nutrient conditions as embryos in culture, show increased risk of elevated blood pressure and metabolic disorders. More recently, our research has focused on many of the mechanisms of embryo responses to poor maternal diet and how these change the subsequent developmental programme and adult health, however, we still do not know how the responses are activated in the first place. If we could discover what precisely induces developmental plasticity in embryos, this information would allow us to devise preventative strategies against adverse health outcomes. We have a substantial body of preliminary data that indicates that the mother utilises the composition of amino acids and possibly insulin within the uterine lumen to communicate to the embryo that nutrient levels are poor which then provokes developmental plasticity in the embryo to enhance survival but leads to adult disease. We will use an embryo in vitro culture model we have developed to mimic conditions within the uterine lumen to modulate this communication pathway and determine precisely the molecular configuration of amino acids and insulin that provoke embryo responses. These responses and impact on later development and adult disease risk will be closely monitored using embryo transfer to foster mothers.This information will allow us to suplement maternal diet in precise ways in an attempt to block adverse developmental programming affecting adult health. A second part of our study concerns a further mechanism mediated by the mother in response to poor maternal diet. Our preliminary data has shown that the uterine wall is induced to generate an increased supply of blood vessels in response to poor diet around the time of implantation. This discovery raises a new concept that the mother can enhance nutient delivery in response to poor diet in early gestation, supplementing the activities mediated by the embryo responses. This maternal response will be characterised fully and assessed whether it is a direct response to dietary signals within the mother or represents the outcome of a signal mediated by the embryo. We will also assess, in quantitative terms, the contribution made by enhanced uterine vascularisation on embryo and fetal survival and growth relative to other aspects of embryo developmental plasticity. These studies on maternal mechanisms associated with developmental programming will provide a powerful resource for developing further dietary/pharmacological strategies to combat adverse gestational induction of disease.