Based upon peer-reviewed scientific observations, our research team has identified the paradigm that the histogenesis and differentiation of the mammalian tooth organ is dependent on sequential, reciprocal epithelial- mesenchymal interactions. We extrapolate that odontogenic tumors, especially the ameloblastoma, represents derangements in these interactions. Understanding the molecular pathogenesis for this group of tumors will provide important insight into normal epithelial-mesenchymal organogenetic interactions and will also provide prognostic markers indicative of aggressive tumor behavior. This competing renewal application represents a logical extension of the scientific goals from the preceding period of support. We will test the hypothesis that the molecular pathogenesis for ameloblastomas is seated in the inappropriate expression of several growth factors and that the perturbation in the spatial and temporal pattern for the expression of these molecules perverts the normal pattern of reciprocal, sequential tissue interactions required for odontogenesis. We will seek to identify prognostic markers for aggressive biological behavior for ameloblastomas by correlating gene expression profiles to tumor history. We will also test the hypothesis that the absence of an enamel extracellular matrix in ameloblastomas is due to the transcription of both the sense and antisense strands of the amelogenin gene, thus preventing amelogenin protein translation. The knowledge gained from analysis of human ameloblastomas will be applied to the analysis of a animal model for these neoplasms. The animal model is based upon the use a novel transgenic animal model which develop odontogenic tumors. The experimental progress by this research group includes i) the development of high resolution in situ hybridization; ii) mRNA phenotyping by RT-PCR; iii) the required experience in molecular biology and molecular genetic techniques and iv) extensive collaboration with preeminent scientists in the field . These qualities suggest that each of the Specific Aims will be successfully completed. We will critically examine our hypothesis through the performance of the following Specific Aims: 1) Perform molecular analysis studies on human ameloblastoma in order to identify differential expression of growth factor gene product(s); 2) Identify and characterize the sense and antisense amelogenin clones from a cDNA library constructed to human ameloblastoma tissue; 3) Define and analyze a mouse transgenic model for human ameloblastoma; and 4) Correlate biological behavior and pattern of differential gene expression between the animal model and the human disease.
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