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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029946-03
Application #
2202310
Study Section
Special Emphasis Panel (SRC (05))
Project Start
1993-01-01
Project End
1996-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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