The long term goal of this program is to determine how growth factor signaling pathways regulate early steps in the development of animal form. We focus on factors and signaling pathways that regulate formation on the nervous system. Projects address fundamental issues in signal transduction using well characterized vertebrate animal mode systems. Pone project has clinical overtones and represents the long term future of our program. Objectives and specific aims are as follows: PDGF and CNTF direct bipotent progenitor cells in the developing rat forebrain toward alternate fates-formation of neurons or formation of astrocytes. Dr. Stiles and colleagues will isolate CNTF and pDGF-inducible """"""""immediate early"""""""" genes that mediate these alternate fates. IGF 1 is an important survival factor for neurons in the rat hind brain. Cr. Greenberg will dissect a novel, PI3 kinase/Akt signaling pathway which is activated by IGF 1 to maintain survival. In both the central and peripheral nervous systems, TGFbeta family members direct the fate choice of multipotent neural progenitor cells. Dr. Whitman and this colleagues will examine the role of mammalian FAST-1 homologues in the regulation of TGFbeta- responsive promoters. PDGF regulates growth, survival and differentiation of glial cells, Dr. Roberts and his colleagues will define the molecular basis of synergy between PDGF and cAMP-PKA ectodermal tumors (PNETs) in children can be conceptualized as multipotent neural progenitor cells that are developmentally stalled. Drs. Pomeroy and Segal will define the role of the neurotrophin receptor Trk C as a prognostic indicator for medulloblastoma (a cerebellar PNET) and also identify genes that are coordinately controlled with TRK C in standard risk versus high risk medulloblastoma. The program faculty have a long and tangible history of productive interaction. They are drawn together by core facilities for phosphotyrosine-directed antibodies, adenovirus expression vectors, and Pediatric Neural Ectodermal Tumor Core.
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