Impaired placental development and function is an underlying cause of intrauterine growth restriction (IUGR), which is a significant cause of infant morbidity and mortality, 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 placental-insufficiency manifests itself in IUGR. The placenta is tasked with transport of oxygen, glucose and amino acids derived from the maternal vasculature to the fetus in support of fetal growth and development, and glucose is the primary energy substrate for placental and fetal oxidative processes. In IUGR pregnancies, transport/transfer of oxygen, glucose and amino acids is deficient, yet the abundance of the glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3) is not reduced in IUGR placenta, at least when assessed in samples collected at delivery. However, functional ablation of either Slc2A1 or Slc2A3 results in embryonic/fetal lethality by 13 days of gestation (dGA). While these results support the requirement of both transporters, there are limitations on the in vivo studies that can be conducted in mice. Historically, the pregnant sheep has provided considerable insight into in vivo placental nutrient uptake, utilization and transfer to the developing fetus. Like the human, sheep SLC2A3 is located on the apical microvillous membrane of the trophoblast, whereas SLC2A1 is located on the basolateral, fetal facing surface. However, the long-standing deficit of sheep as an animal model has been the lack of efficient methods to alter gene expression within the placenta. To that end, we developed and validated in vivo lentiviral-mediated RNA interference, specifically within the placenta, and demonstrated the utility of this technology for two distinct genes (proline-rich 15 and chorionic somatomammotropin/placental lactogen). This approach can now be applied to assess the impact of specific glucose transporter deficiency, in an animal in which future steady- state in vivo investigations can be conducted under non-stressed/non-anesthetized conditions. Herein, we will address our central hypothesis that adequate placental abundance of both SLC2A1 and SLC2A3 is required to provide sufficient glucose transport to the fetus in order to prevent IUGR. We propose two Specific Aims.
In Aim 1 we will test the hypothesis that SLC2A3 deficiency will result in impaired placental development and significant IUGR by mid-gestation (75 dGA).
In Aim2 we will test the hypothesis that SLC2A1 deficiency will result in impaired placental development and significant IUGR by mid-gestation (75 dGA). Use of lentiviral- mediated RNA interference of SLC2A1 and SLC2A3 will not only test our central hypothesis, but will provide a unique animal model to assess the in vivo physiological ramification of placental glucose transport deficiency.

Public Health Relevance

Functional placental insufficiency is a major cause of intrauterine growth restriction, leading to infant morbidity and mortality, and to development of metabolic disease during childhood or later in life. In this proposal, we will use a novel approach to investigate the significance of the two major placental glucose transporters, SLC2A1 and SLC2A3 during the first-half of gestation. This work will provide insight into the relative importance of the two placental glucose transporters, laying the groundwork for extensive in vivo investigations into placental glucose transport and utilization, and enhance our understanding of how functional placental insufficiency results in a significant pregnancy complication.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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Colorado State University-Fort Collins
Other Basic Sciences
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Fort Collins
United States
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