Physiological Ramifications of Chorionic Somatomammotropin Deficiency

项目总结

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.