Steroid regulation of glucose utilization during early pregnancy.

描述（由申请人提供）：患有多囊卵巢综合征（PCOS）、肥胖和胰岛素抵抗的女性植入失败率增加，这导致了这些人群中较高程度的不良妊娠结局。多囊卵巢综合征患者雌激素和胰岛素水平升高被认为是流产发病的重要因素，但其潜在机制尚不清楚。越来越多的数据表明，胰岛素和雌激素水平升高和/或信号传导引起的葡萄糖稳态异常是导致该人群妊娠失败增加的重要因素。此外，这两种激素可能协同作用，改变葡萄糖的利用。多囊卵巢综合征的多因素性质使得解剖所涉及的变量并了解它们对整个疾病的独立贡献非常重要。因此，本研究的目的是进一步了解1)小鼠子宫内膜基质细胞和2)胚胎着床时雌激素介导的、不依赖胰岛素的葡萄糖摄取和代谢变化的分子机制。我们认为，长期暴露于病理水平的雌二醇会通过两种不同的机制干扰子宫内膜基质和着床前胚胎的葡萄糖代谢。在子宫内，雌二醇通过调节孕激素引发的子宫内膜基质细胞中特定葡萄糖转运蛋白的表达来差异性调节葡萄糖摄取。在胚胎中，长期暴露于雌二醇会导致c-Jun nh2末端激酶（JNK）的过度磷酸化，导致胰岛素受体底物-1 （IRS1）失活并产生胰岛素抵抗。本建议的长期目标是剖析病理性高水平雌二醇对葡萄糖利用的影响。我们将利用体外系统研究雌激素在子宫内膜基质细胞和着床前胚胎中的介导作用，然后在雌激素信号增强的体内模型中证实我们的发现。我们将分析子宫基质和胚胎中葡萄糖转运蛋白的表达、葡萄糖的摄取和利用以及胰岛素信号。公共卫生相关性：了解子宫间质和胚胎在这一关键时期对葡萄糖摄取和代谢的激素调节，将有可能促进开发新的药物干预措施，以提高多囊卵巢综合征妇女的成功妊娠率。

DESCRIPTION (provided by applicant): Women with polycystic ovary syndrome (PCOS), obesity, and insulin resistance experience increased rates of implantation failure, which contribute to the higher degree of poor pregnancy outcomes observed in these populations. The increased levels of estrogen and insulin observed in women with PCOS are thought to be important contributors to the pathogenesis of miscarriage, but the underlying mechanisms remain obscure. A growing body of data suggests that abnormalities in glucose homeostasis caused by increased insulin and estrogen levels and/or signaling, are significant contributors to the increased pregnancy failure in this population. In addition, the two hormones may be acting synergistically to alter glucose utilization. The multifactorial nature of PCOS makes it important to dissect the variables involved and understand their independent contributions to the disease as a whole. Therefore, the objective of this proposal is to further understand the molecular mechanisms of estrogen-mediated, insulin-independent changes in glucose uptake and metabolism in 1) the murine endometrial stromal cells and 2) embryo at the time of implantation. We propose that prolonged exposure to pathologic levels of estradiol interferes with glucose metabolism in the uterine endometrial stroma and preimplantation embryo, by two different mechanisms. In the uterus, estradiol differentially modulates glucose uptake by regulating the expression of specific glucose transporters in the progesterone-primed endometrial stromal cells. In the embryo, the prolonged exposure to estradiol leads to hyperphosphorylation of c-Jun NH2-terminal kinase (JNK), leading to inactivation of the insulin receptor substrate-1 (IRS1) and development of insulin resistance. The long term goal of this proposal is to dissect the effects of pathologically high levels of estradiol on glucose utilization. We will utilize in vitro systems to study estrodiol-mediated effects in the endometrial stromal cells and preimplantation embryos and then confirm our findings in an vivo model of increased estrogen signaling. We will analyze glucose transporter expression, glucose uptake and utilization, and insulin signalling in both the uterine stroma and the embryo. PUBLIC HEALTH RELEVANCE: Understanding of the hormonalregulation of glucose uptake and metabolism in the uterine stroma, as well as, in the embryo at this critical time will potentially progress into the development of novel pharmacologic interventions to increase the rate of successful pregnancies in women with PCOS.