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

成人心血管和代谢性疾病的患病率在世界范围内继续以流行病的速度增加。对患者的研究表明，这类疾病的风险因素与产前生活条件有更强的关系，例如产妇营养质量，以及当代生活方式因素。我们使用啮齿动物模型进行的研究表明，胚胎发育的最早阶段，即植入之前，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，这种尝试是为了提高胚胎的存活机会，这被称为“发育可塑性”，但最终会导致成年后患心血管和代谢性疾病的风险增加。有关试管受精儿童的新数据显示，他们在胚胎培养过程中也会经历相对较差的营养条件，他们患高血压和代谢紊乱的风险增加。最近，我们的研究集中在胚胎对不良母亲饮食的许多反应机制，以及这些机制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最初是如何激活的。如果我们能够准确地发现是什么导致胚胎的发育可塑性，这些信息将使我们能够设计出预防不利健康后果的策略。我们有大量的初步数据表明，母亲利用子宫腔内氨基酸的组成，可能还有胰岛素，向胚胎传达营养水平低的信息，这随后会刺激胚胎的发育可塑性，以提高存活率，但会导致成人疾病。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，以调节这一通讯途径，并准确地确定引发胚胎反应的氨基酸和胰岛素的分子配置。这些反应和对以后发育和成人疾病风险的影响将通过胚胎移植寄养母亲来密切监测。这些信息将使我们能够以准确的方式补充母亲的饮食，试图阻止影响成人健康的不利发育规划。我们研究的第二部分涉及母亲对糟糕的母亲饮食做出反应的另一种机制。我们的初步数据表明，在植入前后，不良饮食会诱导子宫壁产生更多的血管供应。这一发现提出了一个新的概念，即母亲可以在怀孕早期因饮食不良而加强营养分娩，补充胚胎反应所介导的活动。这种母体反应将被充分描述并评估它是对母亲体内的饮食信号的直接反应，还是代表由胚胎介导的信号的结果。我们还将在数量上评估，相对于胚胎发育可塑性的其他方面，增强的子宫血管形成对胚胎和胎儿存活和生长的贡献。这些关于与发育规划有关的产妇机制的研究将为制定进一步的饮食/药物战略，以对抗不良妊娠诱发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.