Successful development of the placenta requires coordinated trophoblast and endothelial cell interactions. Indeed, preeclampsia and intrauterine growth retardation (IUGR), the leading causes of maternal and fetal morbidity/mortality, are associated with trophoblast and endothelial cell dysfunction. However, the molecular mechanisms responsible for these functional defects are poorly understood. Our recent findings show that trophoblast produce the potent angiogenic growth factor, placenta growth factor (P1GF), and that P1GF expression is severely reduced in preeclampsia. Furthermore, functional P1GF receptors (flt-1) on trophoblast promote proliferation and inhibit apoptosis in first trimester and term trophoblast, respectively. These data support our hypothesis that aberrant trophoblast production of P1GF contributes to the vascular and trophoblast defects commonly associated with preeclampsia and IUGR. However, the molecular mechanisms regulating trophoblast P1GF expression and autocrine cellular responses are not known. Accordingly, the following specific aims will be used to define the molecular regulation and function of P1GF in trophoblast: l) characterize mechanisms responsible for temporal differences in trophoblast P1GF expression throughout gestation, 2) determine positive and negative regulation of trophoblast P1GF production by select cytokines present at the maternal-fetal interface, 3) determine the mechanistic defects responsible for aberrant P1GF expression in preeclamptic trophoblast, 4) delineate the key signal transduction responses which regulate P1GF autocrine functions in normal trophoblast and, 5) elucidate the functional role of endogenous P1GF in normal trophoblast. Results from these studies will provide critical information regarding the paracrine ability of trophoblast-derived P1GF to regulate vascular function and will produce novel data concerning P1GF as an autocrine factor which influences trophoblast function. Collectively, these aims provide comprehensive insights into the expression, regulation and function of P1GF at the maternal-fetal interface and will facilitate a better understanding of the vascular and trophoblast dysfunctions that are characteristic of preeclampsia and IUGR.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036830-03
Application #
6387990
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
1999-09-01
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$200,226
Indirect Cost
Name
Southern Illinois University Carbondale
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
939007555
City
Carbondale
State
IL
Country
United States
Zip Code
62901
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