Lipids from the maternal circulation are important fetal nutrients and substrates for placental steroid hormone synthesis. However, the mechanisms by which maternal lipids move into and across the human placenta are poorly understood. A striking feature of human pregnancy is the accumulation of VLDL in maternal blood which carries triglycerides, cholesterol, phospholipids as well as lipid-soluble compounds, including tocopherols. The recent discovery that a low-density lipoprotein receptor related protein (LRP), identical to the alpha2 macroglobulin receptor, may participate in the absorptive endocytosis of VLDL particles enriched with apolipoprotein E raised the possibility of an unappreciated mechanism by which the placenta might metabolize VLDL and thus acquire steroidogenic substrates as well as cholesterol, fatty acids and other hydrophobic substances carried by VLDL necessary for fetal growth and development. The investigators propose that the syncytiotrophoblast LRP mediates placental VLDL uptake and that trophoblast production of apolipoprotein E and a 39 kDa endogenous LRP ligand, receptor-associated protein (RAP), modulates the LRP pathway of VLDL metabolism. The hypotheses to be tested are as follows: (1) that the LRP-mediated pathway of absorptive endocytosis provides cholesterol for placental steroid hormone synthesis and fatty acids, cholesterol and lipid soluble substances (e.g., tocopherols) for transport to the fetus and (2) that the LRP pathway is regulated in the placenta through several mechanisms including differentiation-dependent expression of the LRP, apolipoprotein E and RAP genes as cytotrophoblasts differentiate into syncytiotrophoblasts.
The specific aims of the research are as follows: (1) To determine if the LRP mediates uptake of VLDL lipids by normal trophoblast cells and choriocarcinoma cells in culture; (2) To determine the roles of apolipoprotein E and the 30 kDa RAP in modulating LRP function; (3) To determine if trophoblast expression of the LRP gene is associated with differentiation of cytotrophoblasts into syncytiotrophoblasts and to identify effectors of trophoblast LRP gene expression. The role of cell aggregation/fusion in triggering an up- regulation of LRP will be explored and (4) To determine if trophoblast apolipoprotein E and RAP gene expression are coordinately controlled with LRP. The patterns of expression of the proteins and their respective mRNAs will be defined in placental tissue and differentiating trophoblasts in culture. It is hoped that these studies will provide the first comprehensive analysis of the role and regulation of LRP in human placental lipoprotein metabolism and lipid transport.
|Rocca, B; Loeb, A L; Strauss 3rd, J F et al. (2000) Directed vascular expression of the thromboxane A2 receptor results in intrauterine growth retardation. Nat Med 6:219-21|
|Kozarsky, K F; Jooss, K; Donahee, M et al. (1996) Effective treatment of familial hypercholesterolaemia in the mouse model using adenovirus-mediated transfer of the VLDL receptor gene. Nat Genet 13:54-62|
|MacCalman, C D; Furth, E E; Omigbodun, A et al. (1996) Transduction of human trophoblast cells by recombinant adenoviruses is differentiation dependent. Biol Reprod 54:682-91|
|Wittmaack, F M; Gafvels, M E; Bronner, M et al. (1995) Localization and regulation of the human very low density lipoprotein/apolipoprotein-E receptor: trophoblast expression predicts a role for the receptor in placental lipid transport. Endocrinology 136:340-8|
|Matsuo, H; Strauss 3rd, J F (1994) Peroxisome proliferators and retinoids affect JEG-3 choriocarcinoma cell function. Endocrinology 135:1135-45|
|Gafvels, M E; Paavola, L G; Boyd, C O et al. (1994) Cloning of a complementary deoxyribonucleic acid encoding the murine homolog of the very low density lipoprotein/apolipoprotein-E receptor: expression pattern and assignment of the gene to mouse chromosome 19. Endocrinology 135:387-94|
|Coukos, G; Gafvels, M E; Wisel, S et al. (1994) Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and the 39-kd receptor-associated protein in human trophoblasts. Am J Pathol 144:383-92|
|Coukos, G; Gafvels, M E; Wittmaack, F et al. (1994) Potential roles for the low density lipoprotein receptor family of proteins in implantation and placentation. Ann N Y Acad Sci 734:91-102|
|Kido, S; Sakuragi, N; Bronner, M P et al. (1993) D21S418E identifies a cAMP-regulated gene located on chromosome 21q22.3 that is expressed in placental syncytiotrophoblast and choriocarcinoma cells. Genomics 17:256-9|
|Gafvels, M E; Caird, M; Britt, D et al. (1993) Cloning of a cDNA encoding a putative human very low density lipoprotein/apolipoprotein E receptor and assignment of the gene to chromosome 9pter-p23. Somat Cell Mol Genet 19:557-69|
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