Patients heterozygous at the NF1 locus are predisposed to peripheral nerve tumors termed neurofibromas. It is not known which cell types cause neurofibroma formation, if mutations in both NF1 alleles (in one or more cell types) are required for neurofibroma formation, or how cellular and molecular changes subsequent to NF1 mutations lead to neurofibroma formation. To address these issues, the applicant has developed methods to purify Schwann cells and fibroblasts, the major cells types present in neurofibromas, from mice with mutations at the NF1 locus. Both of these cell types show abnormalities. Schwann cells promote angiogenic responses and show diminished responses to mitogens, while fibroblasts fail to fasciculate axons and Schwann cells. It is hypothesized that abnormalities in both cell types result directly from NF1 mutations and are required for neurofibroma formation. The applicant proposes to use purified cells of defined genotype to further characterize mutant phenotypes, with emphasis on testing if alterred production of growth factors underlies the cellular phenotypes, and to test if epigenetic factors augment the phenotypes. Human cells from neurofibromas will be assessed for phenotypes exhibited by mutant mouse cells. Since the NF1 gene product, neurofibromin, is as GTPase- activating protein for Ras, the applicant will attempt to reverse Schwann cell and fibroblast phenotypes with an inhibitor of Ras-GTP. Adult NF1 heterozygotes, in contrast to human patients do not develop neurofibromas. The applicant hypothesizes that null cells (Schwann cells and fibroblasts), together with breach of the perineurium, are required for tumor formation. She will test this hypothesis by determining if tumors form when null cells are grafted into normal rodent peripheral nerves after nerve damage, or if wounding of NF1 heterozygote nerves is sufficient to promote tumor formation.
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