Successful investigations into the pathogenesis of cleft palate are hampered by an incomplete understanding of normal craniofacial ontogenesis in general and the secondary palate in particular. Investigations dealing with characterization and regulation of basic developmental processes involved in normal craniofacial morphogenesis and dysmorphogenesis, therefore, are essential in that they contribute significantly toward the biological foundation necessary to design experiments aimed at clarifying the etiology of facial clefts. Several hormonal primary messengers are capable of regulating developmentally significant biological responses in palatal tissue by modulating intracellular levels of cAMP. The effects of cAMP on metabolic pathways in eukaryotes are mediated by cAMP- dependent protein kinases (cAMP-dPKs) which in turn phosphorylate regulatory proteins. Levels of activity or distribution of cAMP-PKs in response to hormones have not been investigated in the embryonic orofacial region. The notion that changes in the amounts or subcellular distribution of cAMP-PKs activities subsequent to hormone stimulation is supported by studies in other tissue. That these alterations can be recognized by palatal cells as signals which may regulate the cells metabolic response during orofacial ontogenesis is an intriguing possibility. The overall goal of this application is: 1) Characterizing the intracellular response of cAMP-PKs in embryonic cells derived from the oro-facial region subsequent to specific hormonal stimulation, and 2) Determination of a role for R1 or R11 in palate epithelial differentiation, 3) Determination if palate mesenchymal cell GAG synthesis is a cAMP-dPK mediated event, and 4) Analysis of an intracellular effector (ODC) thought to mediate hormonal modulation of embryonic palatal cell proliferation and glycosaminoglycan synthesis. These studies will provide us with a working model to investigate mechanisms underlying cellular pleiotropic hormonal responsiveness of this embryonic oro-facial tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE008199-01A1
Application #
3222013
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1988-07-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Weston, W M; Greene, R M (1995) Developmental changes in phosphorylation of the transcription factor CREB in the embryonic murine palate. J Cell Physiol 164:277-85
Nugent, P; Potchinsky, M; Lafferty, C et al. (1995) TGF-beta modulates the expression of retinoic acid-induced RAR-beta in primary cultures of embryonic palate cells. Exp Cell Res 220:495-500
Greene, R M; Lloyd, M R; Uberti, M et al. (1995) Patterns of cyclic AMP-dependent protein kinase gene expression during ontogeny of the murine palate. J Cell Physiol 163:431-40
Nugent, P; Greene, R M (1994) Interactions between the transforming growth factor beta (TGF beta) and retinoic acid signal transduction pathways in murine embryonic palatal cells. Differentiation 58:149-55
Gehris, A L; Pisano, M M; Nugent, P et al. (1994) Regulation of TGF beta 3 gene expression in embryonic palatal tissue. In Vitro Cell Dev Biol Anim 30A:671-9
Gawel-Thompson, K J; Greene, R M (1992) Quantification and localization of ornithine decarboxylase in the embryonic palate. J Exp Zool 261:441-50
Greene, R M; Lloyd, M R; Pisano, M M (1992) Cyclic AMP-dependent protein kinase in human embryonic palate mesenchymal cells. In Vitro Cell Dev Biol 28A:755-62
Gehris, A L; Greene, R M (1992) Regulation of murine embryonic epithelial cell differentiation by transforming growth factors beta. Differentiation 49:167-73
Weston, W M; Greene, R M (1991) Effects of ethanol on cAMP production in murine embryonic palate mesenchymal cells. Life Sci 49:489-94

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