Physiological Ramifications of Chorionic Somatomammotropin Deficiency

绒毛膜生长激素缺乏的生理影响

• 批准号: 9921441
• 负责人: RUSSELL V ANTHONY
• 金额: $ 58.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-13 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921441
• 关键词: Address; Adult; Adverse effects; Amino Acid Transporter; Amino Acids; Animal Model; B-Cell Development; Blood Circulation; Blood flow; Catheters; Childhood; Chronic; Coronary heart disease; Data; Depressed mood; Development; Diabetes Mellitus; Endocrine; Etiology; Exhibits; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Liver; Fetal Tissues; Fetal Weight; Fetus; GLUT-3 protein; Gestational Age; Glucose; Goals; Growth; Growth Factor; Growth and Development function; Hepatic; Hepatocyte; Hormones; Human; Hypertension; IGF2 gene; IGFBP2 gene; Impairment; In Vitro; Individual; Infant Mortality; Infusion procedures; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Islet Cell; Islets of Langerhans; Lead; Life; Link; Measures; Messenger RNA; Metabolic Diseases; Methodology; Methods; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Oxygen; Pancreas; Pathogenesis; Physiological; Physiology; Placenta; Placental Hormones; Placental Insufficiency; Placental Lactogen; Placentation; Plasma; Pregnancy; Pregnancy Complications; Production; Proteins; RNA Interference; Regulation; Role; SLC2A1 gene; Sheep; Stroke; Structure of umbilical artery; Testing; Umbilical Blood; Uterus; Weight; Work; fetal; gene function; glucose transport; in vivo; infant morbidity; infant morbidity/mortality; innovation; insulin secretion; insulin sensitivity; islet; lentiviral-mediated; novel; paracrine; public health relevance; uptake

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.

项目概要 胎盘发育和功能受损是宫内生长受限 (IUGR) 的根本病因， 这是婴儿死亡率和发病率的一个重要原因，使这些人易于成年代谢 疾病，包括 2 型糖尿病。不幸的是，人类的进步仍然有很多方面 不了解的怀孕，特别是关于怀孕的原因和进展 因胎盘发育受损而变得复杂。其中许多问题无法直接解决 人类，预测对相关动物模型的需求。找出原因是我们的长期目标 胎盘功能受损背后的原因及其在 IUGR 中的表现。为此，我们在vivo开发了 慢病毒介导的RNA干扰方法，以评估慢病毒表达的基因的功能 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。绒毛膜生长激素 (CSH) 被发现超过 50 年 以前，是胎盘分泌最丰富的蛋白质之一，但没有直接证据 定义其功能。慢病毒介导的 RNA 干扰导致绵羊妊娠缺乏 CSH 近期表现出明显的胎盘和胎儿生长受限，并且胎儿生长受限在 怀孕前三分之一结束。缺乏 CSH 的妊娠中的近期胎儿是 低胰岛素血症和低 IGF1。营养转运蛋白的胎盘表达，尤其是 SLC2A1 (GLUT1) 妊娠早期减弱，并且 SLC2A1 和 SLC2A3 (GLUT3) 近期均显着抑制， 表明 CSH 缺乏导致的 IUGR 可能是（至少部分）受损的结果 胎盘营养转移。在这里，我们将提出我们的中心假设，即 CSH 具有双重机制 调节胎儿生长的作用：1）刺激胎盘发育和向胎儿输送营养，2） 它还直接刺激妊娠早期至中期和循环中胎儿组织旁分泌 IGF1 和 2 的表达 （内分泌）IGF1 和妊娠晚期胰岛素的产生。这个假设得到了我们令人信服的支持 初步数据和研究稳态非稳态条件下 CSH 缺乏后果的能力 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 在 CSH 缺乏的妊娠中观察到的妊娠早期和中期 IUGR 是胎盘受损的结果 葡萄糖转移至胎儿并损害胎儿组织 IGF1 和 2 表达的刺激。在目标 2 中，我们将 检验以下假设：妊娠晚期 IUGR 观察到的 CSH 缺乏是由于胎盘受损造成的 葡萄糖转移至胎儿并降低胎儿循环胰岛素和 IGF1 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IGF1和胰岛素。这些创新和稳健的研究相结合将 显着影响我们对导致 IUGR 的体内胎盘-胎儿相互作用的理解。