Pre-conception obesity programs placental inflammation and function

 描述（由申请人提供）：患有妊娠糖尿病（GDM）的女性在产后数年和数十年内几乎不变地发展为2型糖尿病。除了糖尿病给女性带来的风险外，微血管和大血管疾病是最常见的，GDM还可能对发育中的胎儿产生不良后果，导致巨大儿和分娩并发症，以及代谢紊乱、肥胖和神经认知障碍的终生风险增加。胎盘被认为在GDM的发展中起主要作用，因为该组织合成并分泌促炎细胞因子，导致全身炎症增加，这是GDM的标志。目前的观点认为，胎盘炎症增加是母体环境的结果，包括全身炎症增加。然而，我们现在有了令人兴奋的初步数据，通过证明胎盘在妊娠期间暴露于母体环境之前就已经被编程为发生炎症来挑战这一教条。使用胚胎移植技术，我们已经证明，与来自瘦女性胚胎的胎盘相比，来自肥胖女性胚胎的胎盘植入到天真女性体内的炎症增加。由于肥胖妇女和啮齿类动物的卵母细胞功能障碍，氧化应激增加，线粒体改变，这并不是完全出乎意料的。虽然目前许多改善肥胖妇女和GDM妇女妊娠结局的措施都是针对孕妇的，但我们的数据表明，应针对孕前环境。根据我们的初步数据，我们的中心假设是，怀孕前母亲肥胖程序卵母细胞产生过度炎症和功能受损的胎盘。我们将用两个目标来检验我们的假设。目标1。确定是否孕前肥胖程序胎盘炎症和功能。在这个目标中，我们将从第一次或第四次怀孕的女性身上移植胚胎到天真的女性身上。将在胎盘和母体组织中评估炎症级联反应的激活，以及母体胰岛素抵抗。还将测量胎盘营养转运。年龄和怀孕对胎盘编程的贡献也将被剖析出来。目标2.确定怀孕后母亲肥胖对胎盘炎症和功能的作用。再次使用胚胎移植技术，我们将确定受孕前卵母细胞环境是否编程胎盘如何受到受孕后环境的影响。我们将研究炎症和功能的胎盘来自胚胎瘦或肥胖的女性，并转移到MIO代孕母亲。这些研究的基本原理是，它们可能导致新的目标，即干预的最佳时间，旨在降低GDM发展的风险和由于胎盘炎症和功能障碍导致的不良妊娠结局。

 DESCRIPTION (provided by applicant): Women with Gestational Diabetes Mellitus (GDM) have the almost invariable development of type 2 diabetes in the years and decades post-partum. Beyond the risk diabetes confers on these with women, with microvascular and macrovasular disease the most common, GDM can also have adverse consequences to the developing fetus, causing macrosomia and complications at delivery, as well as increased lifetime risk of metabolic disorders, obesity, and neurocognitive impairments. The placenta is thought to play a major role in the development of GDM because this tissue synthesizes and secretes pro-inflammatory cytokines, leading to increased systemic inflammation, a hallmark of GDM. The current viewpoint holds that increased placental inflammation is a consequence of the maternal environment, including increased systemic inflammation. However, we now have exciting preliminary data that challenges this dogma by demonstrating that the placenta is already programmed to develop inflammation prior to exposure to the maternal environment during gestation. Using embryo transfer technology we have shown that placentas derived from embryos collected from obese females and implanted into naïve females have increased inflammation compared to placentas derived from embryos of lean females. Because oocytes of obese women and rodents are dysfunctional with increased oxidative stress and altered mitochondria, it is not completely unexpected. Though many of the current practices to improve pregnancy outcomes of obese women and women with GDM are targeted to the pregnant female, our data suggest that the pre-pregnancy environment should be targeted. Based on our preliminary data, our central hypothesis is that pre-conception maternal obesity programs oocytes to give rise to placentas with excessive inflammation and impaired function. We will test our hypothesis with 2 aims. Aim 1. Determine if pre-conception obesity programs placental inflammation and function. In this aim, we will transfer embryos from females in their 1st or 4th pregnancy into naïve females. Activation of inflammatory cascades will be assessed in placentas and maternal tissues, as will maternal insulin resistance. Placental nutrient transport will also be measured. Contributions of aging and pregnancies to placental programming will be dissected out as well. Aim 2. Determine the role of post-conception maternal obesity on placental inflammation and function. Once again using embryo transfer technology, we will determine if pre-conception oocyte environment programs how placentas are affected by post- conception environment. We will examine inflammation and function in placentas derived from embryos of lean or obese females and transferred into MIO surrogate mothers. The rationale for these studies is that they could lead to new targets, i.e. optimal times for interventions, aimed a decreasing the risk of GDM development and adverse pregnancy outcomes due to placental inflammation and dysfunction.