The mechanisms of trophoblast proliferation and invasion are likely to involve the expression of specific growth factors. The platelet-derived growth factor (PDGF) system in mesenchymal cells consists of three components: 1) the hormone (PDGF); 2) the receptor (PDGF-R) and 3) post-receptor pathways. PDGF induces mitogenesis by first interacting with specific receptor (PDGF-R) sites on the surface or responsive cells. A variety of intracellular mediators are subsequently activated, resulting in the enhanced expression of a family of growth promoting genes, including the proto-oncogenes c-sis, c-myc, and c-fos. Rapidly proliferating cytotrophoblasts in first trimester human placenta have been shown to bind [125I]PDGF and express c-sis and c-myc transcripts. Nonproliferating syncytiotrophoblast, in contrast, appears to have none of these characteristics. The mechanisms by which sensitivity to PDGF in the placenta is conferred and withdrawn are completely unknown, but are likely to involve the expression of the PDGF-R or pre- or post-receptor events.
The specific aims are designed to describe the ontogeny and modulation of PDGF action during placental invasion and differentiation. The hypothesis is that growth factor regulation in developing trophoblast is programmed by the state of cellular differentiation. The work identifies markers for each of the three potential levels of regulation. During the first two years of study, each of the three components of the PDGF system will be quantified in developing human and house placentae. The hormone will be evaluated by measuring the expression of the proto-oncogene homologue of PDGF, c-sis. The receptor and a product of the post-receptor pathway, c-myc will also be measured, using sensitive RNase protection assays. Work will continue on the optimization of in situ hybridization assays to localize the distribution of c-sis, PDGF-R, and c-myc transcripts. In the third and fourth year of research, an in vitro model of trophoblastic differentiation will be established to analyze the ability of maternal or placental products (e.g. PDGF, human chorionic gonadotropin [hCG], thrombin, pregnancy serum, steroid hormones) to modulate c-sis, c-myc, and PDGF-R expression in differentiating cytotrophoblasts. Established endocrine markers of trophoblast differentiation (e.g. hCG, human placental lactogen, progesterone) will be examined using histochemical techniques to assess the possible co-regulation of proliferative and endocrine activities in these cells. In the fifth year of support, specific steps along the biochemical pathways of PDGF action will be examined, including the potential roles of phosphoinositide turnover, turnover, protein kinase C activation, and calcium mobilization. This model of mitogenesis in normal cells will elucidate mechanisms of cellular proliferation that may be aberrant in transformed or malignant cells. In addition, an understanding of the factors involved in normal placentation can be used to design clinically useful inhibitors of implantation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HD022873-01
Application #
3469469
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1987-06-01
Project End
1992-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Baker, V L; Murai, J T; Taylor, R N (1998) Downregulation of protein kinase C by phorbol ester increases expression of epidermal growth factor receptors in transformed trophoblasts and amplifies human chorionic gonadotropin production. Placenta 19:475-82
Kilpatrick, S J; Roberts, J M; Lykins, D L et al. (1993) Characterization and ontogeny of endothelin receptors in human placenta. Am J Physiol 264:E367-72
Rothman, P A; Chao, V A; Taylor, M R et al. (1992) Extraplacental human fetal tissues express mRNA transcripts encoding the human chorionic gonadotropin-beta subunit protein. Mol Reprod Dev 33:1-6
Kratzer, P G; Golbus, M S; Finkelstein, D E et al. (1991) Trisomic pregnancies have normal human chorionic gonadotropin bioactivity. Prenat Diagn 11:1-6
Taylor, R N; Newman, E D; Chen, S A (1991) Forskolin and methotrexate induce an intermediate trophoblast phenotype in cultured human choriocarcinoma cells. Am J Obstet Gynecol 164:204-10
Taylor, R N; Musci, T J; Rodgers, G M et al. (1991) Preeclamptic sera stimulate increased platelet-derived growth factor mRNA and protein expression by cultured human endothelial cells. Am J Reprod Immunol 25:105-8
Taylor, R N; Musci, T J; Kuhn, R W et al. (1990) Partial characterization of a novel growth factor from the blood of women with preeclampsia. J Clin Endocrinol Metab 70:1285-91
Taylor, R N; Heilbron, D C; Roberts, J M (1990) Growth factor activity in the blood of women in whom preeclampsia develops is elevated from early pregnancy. Am J Obstet Gynecol 163:1839-44
Musci, T J; Roberts, J M; Rodgers, G M et al. (1988) Mitogenic activity is increased in the sera of preeclamptic women before delivery. Am J Obstet Gynecol 159:1446-51
Taylor, R N; Williams, L T (1988) Developmental expression of platelet-derived growth factor and its receptor in the human placenta. Mol Endocrinol 2:627-32