The overall aim of this proposal is to understand the placental nutrient mechanisms that regulate fetal growth. GLUT 3, a specific facilitative glucose transporter is expressed in the trophoectoderm/trophoblasts of the placenta and along with GLUT 1 coordinately mediates trans-placental glucose transport to the conceptus. Normal development (D) causes an increase in placental GLUT 3 expression and concentrations in late gestation associated with maximal fetal growth, while maternal nutrient restriction (MNR) or specific growth factor deficiency (EGF) leads to a decline in placental GLUT 3 concentrations with fetal growth restriction. We have observed that GLUT 3 is transcriptionally regulated by cis elements that bind dephosphorylated Sp1/Sp3 in rat trophoblast cells (HRP.1). To pursue an in-vivo extension of these novel in-vitro observations, we have created a GLUT 3-luciferase transgenic mouse and a mouse model of MNR. Further to investigate the functional significance of trophoectoderm/placental GLUT 3 we created a GLUT 3 null mouse, the heterozygote demonstrates fetal growth restriction which is associated with cellular apoptosis/necrosis. To define the role of placental GLUT 3 during D and in response to MNR, the proximate goal of this proposal is to test the hypothesis that placental GLUT 3 expression is critical for fetal glucose supply through development and MNR, and the absence of GLUT 3 predisposes towards aberrant trophoblast and thereby fetal cellular proliferation, differentiation, apoptosis, and/or necrosis. To test this hypothesis, we propose three specific aims: 1] To determine the mechanism(s) by which D and MNR regulates placental GLUT 3 expression, we plan to employ the GLUT 3-luciferase transgenic mouse lines and investigate the effect of D and MNR on transcriptional regulation of GLUT 3, 2] To explore the effect of decreased GLUT 3 concentrations on normal placental and fetal D and in MNR, we will employ the GLUT 3 null heterozygous mouse line (50%), and determine the effect on placental and fetal phenotype and function, and 3] To investigate the functional role of GLUT 3 on normal placental and fetal D and in MNR, we will examine homozygous null GLUT 3 pre-implantation embryos, and employ the Tet-Off system to repress GLUT 3 expression in a recombinant mouse strain, and examine the effect on placental and fetal phenotype. Our proposed studies will define the biological role of GLUT 3 in normal and aberrant fetal growth. ? ?
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