Normal human fetal growth and development depend upon a highly regulated cascade of developmental events leading to hemochorial placentation, establishment of uteroplacental contacts and, in late gestation, preparation for perinatal transition. In placenta, the processes of trophoblast proliferation, migration, differentiation, cell fusion and apoptosis are collapsed into the period of gestation. This provides a unique model to study the genes which direct these key maturational events. In addition, abnormal trophoblast differentiation and invasiveness are associated with several common disorders of pregnancy such as intrauterine growth restriction (IUGR), preeclampsia, early pregnancy loss and placenta accreta. We have shown that certain features of human trophoblast differentiation in vivo can be recapitulated in vitro. In preliminary studies we also have uncovered regulatory roles during human trophoblast development for two endogenous polypeptides, the hormone calcitonin and the hormonally-stimulated cytokine interleukin-11 (IL-11). We hypothesize that these factors represent novel physiological modulators of trophoblast differentiation through their actions on trophoblast regulatory genes. We will investigate the effects of these specific factors and their signaling pathways upon trophoblast proliferation, migration and invasiveness, endocrine function and syncytium formation. We also will examine cell cycle regulators involved with differentiation of myoblasts (which also undergo syncytium formation) and hepatocyte cell cycle regulators identified in Subproject I for their effects on trophoblast differentiation. We will identify cell cycle inhibitors and other novel genes differentially regulated during hormone- stimulated trophoblast differentiation. We will isolate and clone these differentially regulated cDNAs and investigate their temporal and cell specific expression during placental development and in pathological samples. The identification of the role of these mechanisms of placental differentiation will provide new pathophysiologic insights into development.

Project Start
1998-07-01
Project End
1999-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Women and Infants Hospital-Rhode Island
Department
Type
DUNS #
069851913
City
Providence
State
RI
Country
United States
Zip Code
02905
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Tseng, Yi-Tang; Wadhawan, Rajan; Stabila, Joan P et al. (2002) Molecular interactions between glucocorticoid and catecholamine signaling pathways. J Allergy Clin Immunol 110:S247-54
Tseng, Y T; Kopel, R; Stabila, J P et al. (2001) Beta-adrenergic receptors (betaAR) regulate cardiomyocyte proliferation during early postnatal life. FASEB J 15:1921-6
McNab, T C; Tseng, Y T; Stabila, J P et al. (2001) Liganded and unliganded steroid receptor modulation of beta 1 adrenergic receptor gene transcription. Pediatr Res 50:575-80
Tseng, Y T; Stabila, J P; Nguyen, T T et al. (2001) A novel glucocorticoid regulatory unit mediates the hormone responsiveness of the beta1-adrenergic receptor gene. Mol Cell Endocrinol 181:165-78
Tseng, Y T; Stabila, J; McGonnigal, B et al. (1998) An inverted cAMP response element mediates the cAMP induction of the ovine beta 1-adrenergic receptor gene. Biochem Mol Biol Int 46:1127-34