GROWTH FACTOR REGULATION OF CELL DIFFERENTIATION

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Successful investigations into the pathogenesis of cleft palate are hampered by an incomplete understanding of normal craniofacial ontogenesis in general and secondary palate formation 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. Although TGF-beta was initially described based on its ability to reversibly induce phenotypic transformation of fibroblastic cells, what has since emerged, is a concept of TGF-beta as a multifunctional regulatory peptide, involved in many developmental processes and controlling both growth and differentiation in an ever increasing diversity of cell and tissue types. In order to begin to examine the possible role that TGF-beta may play in palatal development, we are proposing to determine the relative amounts and localization of both TGF-beta and its mRNA in this embryonic tissue, investigate factors which may be responsible for positively and negatively regulating its action and characterize TGF-beta receptors_during palatal ontogeny. Cellular proliferation and synthesis of extracellular glycosaminoglycans and collagen has been shown to play a critical role in the normal ontogeny of the mammalian palate. The ability of TGF-beta to modulate extracellular matrix (ECM) accumulation is well documented and we propose to investigate the functional nature of these multifunctional molecules by determining 1) whether growth and/or synthesis of ECM components by cells derived from the developing embryonic palate are TGF-beta-mediated processes utilizing antisense oliaonucleotides to block expression of genes encoding for TGF-betas and 2). whether TGF-beta is capable of regulating ECM accumulation in embryonic palatal tissue either at the level of synthesis and/or degradation. The specific aims of this application include: 1- Determination of relative amounts and localization of TGF-beta in embryonic palatal tissue in vivo and in vitro, 2 - Determination of relative steady state levels, rates of transcription and localization of mRNA's for TGF-beta1, TGF-beta2 and TGF-beta3, 3 - Determination of whether growth and/or synthesis of ECM by embryonic palatal cells are TGF-beta-mediated processes, 4 - Characterization of TGF-beta receptors in developing palatal tissue and 5 - Analysis of biological responsiveness of embryonic palatal tissue to TGF-beta.