Craniofacial malformations occur with a frequency of 1 in 600 live births annually in the United States. Since the causes of abnormal formation of the palate are largely unknown, basic science research into the molecular regulatory mechanisms responsible for normal development of the palate is essential in order to provide the framework for investigations into the etiology of palatal clefts. Our previous studies have provided documentation of unique temporal and spatial patterns of expression of the transforming growth factors beta (TGFbetas) and their receptors as well as the ability of the TGFbetas to regulate proliferation and metabolism of several extracellular matrix components in developing palatal tissue. Substantial evidence supports the premise that various signal transduction systems interact to regulate cell proliferation and cell differentiation during embryogenesis. Such interactions represent the underpinnings of complex and delicately balanced developmental systems. The studies outlined in this application propose to demonstrate that several signaling molecules are components of a coordinated regulatory system, wherein several different signaling pathways integrate with one another. Such a regulatory system thereby provides multiple levels of regulation and exquisite control of gene expression in embryonic palatal tissue. The current application will extend the findings of the previous funding period and proposes specific studies to examine; the amounts of mature biologically active TGFbeta and various latent complexes of TGFbeta protein synthesized during development of the palate (aim #1, factors that regulate synthesis of TGFbeta isoforms (aim #2) and their receptors (aim #4) in embryonic palatal tissue, whether intracellular TGFbeta-mediated signal transduction is mediated bia protein phosphorylation (aim #5), and how this signal transduction pathway interacts with the retinoic acid signaling pathway, also relevant to embryonic orofacial development (aim #3). Molecular analyses of gene function in the embryo utilizing the developing craniofacial region, thus promise definition and clarification of developmental pathways critical for normal embryogenesis as well as identification of foci for perturbation and attendant craniofacial dysmorphogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE009540-07
Application #
2391209
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1991-04-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1999-03-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Nugent, P; Greene, R M (1998) Use of antisense oligonucleotides to study the role of CRABPs in retinoic acid-induced gene expression. Methods Mol Biol 89:191-202
Weston, W M; Potchinsky, M B; Lafferty, C M et al. (1998) Cross-talk between signaling pathways in murine embryonic palate cells: effect of TGF beta and cAMP on EGF-induced DNA synthesis. In Vitro Cell Dev Biol Anim 34:74-8
Potchinsky, M B; Lloyd, M R; Weston, W M et al. (1998) Selective modulation of MAP kinase in embryonic palate cells. J Cell Physiol 176:266-80
Potchinsky, M B; Weston, W M; Lloyd, M R et al. (1997) TGF-beta signaling in murine embryonic palate cells involves phosphorylation of the CREB transcription factor. Exp Cell Res 231:96-103
Potchinsky, M; Nugent, P; Lafferty, C et al. (1996) Effects of dexamethasone on the expression of transforming growth factor-beta in mouse embryonic palatal mesenchymal cells. J Cell Physiol 166:380-6
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
Weston, W M; Nugent, P; Greene, R M (1995) Inhibition of retinoic-acid-induced gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Biophys Res Commun 207:690-4
Nugent, P; Greene, R M (1995) Antisense oligonucleotides to CRABP I and II alter the expression of TGF-beta 3, RAR-beta, and tenascin in primary cultures of embryonic palate cells. In Vitro Cell Dev Biol Anim 31:553-8
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

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