Physiological Ramifications of Chorionic Somatomammotropin Deficiency

项目摘要 胎盘发育和功能受损是宫内生长受限（IUGR）的潜在病因， 这是婴儿死亡率和发病率的重要原因，使这些个体易患成人代谢性疾病， 2型糖尿病是什么？不幸的是，人类的进步还有很多方面， 不了解的怀孕，特别是关于怀孕的原因和进展 并发胎盘发育受损。其中许多问题无法直接在 人类，预测需要相关的动物模型。我们的长期目标是确定 胎盘功能受损的背后，以及这在IUGR中的表现。为此，我们在体内开发了 慢病毒介导的RNA干扰方法，以评估表达的基因的功能， 绵羊胎盘，一种允许在稳态下研究胎盘和胎儿生理学的动物模型 非麻醉/非应激条件。绒毛膜促生长激素（CSH）发现50多年 是胎盘分泌的最丰富的蛋白质之一，但没有直接证据表明 定义其功能。慢病毒介导的RNA干扰在绵羊中产生的FSH缺乏妊娠 近期表现出明显的胎盘和胎儿生长受限，胎儿生长受限在 怀孕的前三分之一结束。在我们缺乏GSH的妊娠中， 低胰岛素血症和低IGF 1。胎盘中营养转运蛋白的表达，特别是SLC 2A 1（GLUT 1）， 在妊娠早期减少，并且SLC 2A 1和SLC 2A 3（GLUT 3）在近期都显著降低， 这表明CSH缺乏导致的IUGR可能是一个结果，至少部分是由于受损的， 胎盘营养转移在此，我们将讨论我们的中心假设，即CSH具有双重机制， 在调节胎儿生长中的作用：1）它刺激胎盘发育和向胎儿输送营养，以及2） 它还直接刺激胎儿组织旁分泌IGF 1和2的表达， （内分泌）IGF 1和胰岛素生产在妊娠后期。这一假设得到了我们令人信服的支持。 初步的数据和能力，研究的后果，CSH缺乏下稳态非 麻醉/非应激条件。我们提出三个具体目标。在目标1中，我们将检验假设 GSH缺乏妊娠中观察到的妊娠早期和中期IUGR是由胎盘功能受损引起的， 葡萄糖转移到胎儿和受损的刺激胎儿组织IGF 1和2的表达。在目标2中， 验证CSH缺乏导致妊娠晚期IUGR是胎盘功能受损的假设。 葡萄糖转移到胎儿和较低的胎儿循环胰岛素和IGF 1浓度。在目标3中，我们将测试 妊娠晚期CSH缺乏导致体外和/或体内肝细胞和胰岛受损的假设 分别分泌IGF 1和胰岛素。这些创新和强大的研究相结合， 显著影响我们对导致IUGR的体内胎盘-胎儿相互作用的理解。

PROJECT SUMMARY Impaired placental development and function is an underlying etiology of intrauterine growth restriction (IUGR), which is a significant cause of infant mortality and morbidity, predisposing these individuals to adult metabolic disease, including Type 2 Diabetes. Unfortunately, there are still many aspects of the progression of human pregnancy that are not understood, especially in regards to the causation and progression of pregnancies complicated by impaired placental development. Many of these questions cannot be directly addressed in humans, predicating the need for relevant animal models. It is our long-term goal to determine the causes behind impaired placental function, and how this manifests itself in IUGR. To this end, we developed in vivo lentiviral-mediated RNA interference methodologies in order to assess the function of genes expressed by the placenta in sheep, an animal model that allows the study of placental and fetal physiology under steady state non-anesthetized/non-stressed conditions. Chorionic Somatomammotropin (CSH) was discovered >50 year ago, and is one of the most abundant proteins secreted by the placenta, yet there is no direct evidence defining its function. CSH-deficient pregnancies, generated by lentiviral-mediated RNA interference in sheep exhibit significant placental and fetal growth restriction near-term, and the fetal growth restriction is apparent at the end of the first one-third of pregnancy. The near-term fetuses in our CSH-deficient pregnancies are hypoinsulinemic and hypo-IGF1. Placental expression of nutrient transporters, especially SLC2A1 (GLUT1) is diminished early in pregnancy, and both SLC2A1 and SLC2A3 (GLUT3) are significantly depressed near-term, suggesting that the IUGR resulting from CSH deficiency may be a consequence, at least in part, from impaired placental nutrient transfer. Herein, we will address our central hypothesis that CSH has a dual mechanistic role in regulating fetal growth: 1) it stimulates placental development and nutrient transport to the fetus, and 2) it also directly stimulates fetal tissue paracrine IGF1 and 2 expression in early to mid-gestation and circulating (endocrine) IGF1 and insulin production in late-gestation. This hypothesis is supported by our compelling preliminary data and the ability to study the ramifications of CSH deficiency under steady state non- anesthetized/non-stressed conditions. We propose three Specific Aims. In Aim 1 we will test the hypothesis that early- and mid-gestation IUGR observed in CSH-deficient pregnancies results from impaired placental glucose transfer to the fetus and impaired stimulation of fetal tissue IGF1 and 2 expression. In Aim 2 we will test the hypothesis that late-gestation IUGR observed with CSH deficiency results from impaired placental glucose transfer to the fetus and lower fetal circulating insulin and IGF1 concentrations. In Aim 3 we will test the hypothesis that late-gestation CSH deficiency causes impaired in vitro and/or in vivo hepatocyte and islet secretion of IGF1 and insulin, respectively. The combination of these innovative and robust studies will significantly impact on our understanding of in vivo placental-fetal interactions that result in IUGR.