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.
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