Three inter-related RO- 1 grants are proposed to elucidate the pathogenesis of preeclampsia, an obstetrical disease affecting as many as 10% of women in their first pregnancy. This disease, characterized by hypertension, edema, and proteinuria, is frequently complicated by thrombocytopenia, liver and kidney lesions and in its severest form, widespread intravascular coagulopathy, seizures and death. The three projects will test the hypothesis that dysregulation of the urokinase plasminogen activator system and the alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein system account for the deficient invasion of trophoblast cells into the endometrium and failure of the remodeling of the uterine spiral arteries, which are histopathologic hallmarks of preeclampsia. The second hypothesis is that placental hypoxemia, a consequence of the retention of smooth muscle around uterine arteries and release of vasoconstrictor substances affects placental function and leads to release of additional vasoactive substances that increase blood pressure and activate platelets. The three projects bundled in response to this RFA are complimentary in their specific aims and utilize related methodologies. They will examine the regulation and role of the urokinase and alpha2-macroglobulin receptor systems in normal and preeclamptic pregnancies using biochemical and immunohistochemical techniques. The functional activities of these proteins will be examined utilizing model in vitro of trophoblast invasion. The collaborative approach will provide opportunities for synergistic interactions that will speed the completion of research goals and lead to new understanding of the pathophysiology of a disease that causes significant morbidity and mortality in young women.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050786-02
Application #
2227085
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S2))
Project Start
1993-09-30
Project End
1998-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Parry, S; Holder, J; Halterman, M W et al. (1998) Transduction of human trophoblastic cells by replication-deficient recombinant viral vectors. Promoting cellular differentiation affects virus entry. Am J Pathol 152:1521-9
Parry, S; Holder, J; Strauss 3rd, J F (1997) Mechanisms of trophoblast-virus interaction. J Reprod Immunol 37:25-34
MacCalman, C D; Furth, E E; Omigbodun, A et al. (1996) Regulated expression of cadherin-11 in human epithelial cells: a role for cadherin-11 in trophoblast-endometrium interactions? Dev Dyn 206:201-11
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
Sakuragi, N; Matsuo, H; Coukos, G et al. (1994) Differentiation-dependent expression of the BCL-2 proto-oncogene in the human trophoblast lineage. J Soc Gynecol Investig 1:164-72
Landers, J E; Haines, D S; Strauss 3rd, J F et al. (1994) Enhanced translation: a novel mechanism of mdm2 oncogene overexpression identified in human tumor cells. Oncogene 9:2745-50