Platelet derived growth factors (PDGFs) are required the formation of oligodendrocytes, neural crest, vascular smooth muscle and a variety of cell types of mesenchymal origin, and the deregulation of this pathway has been implicated in disease and in various cancers. However, the critical targets of this pathway remain for the most part unknown. This proposal will follow three independent but synergistic approaches that are united conceptually by virtue of searching for new factors that operate in the PDGF signaling pathway. First, we will identify genes whose expression is regulated in response to PDGF and generate and analyze the corresponding mutant mice. The screen will be performed using high-density microarrays using two cell types which exhibit critical dependence on PDGF signaling, primary palatal mesenchymal cells and oligodendrocyte precursor cells. PDGF target gene mutants will be obtained from the existing collection of gene trap lines available in the laboratory or generated using conditional gene trap vectors, or through the international mouse mutagenesis consortium. Priority will be given to identifying transcription factors regulated by PDGF, to identify a nuclear signature pathway for PDGF signaling. Second, we will identify primary protein targets that become phosphorylated in response to PDGF, using primary palatal mesenchymal cells and oligodendrocyte precursor cells. Following treatment with PDGF, phosphorylated tryptic peptides will be identified by mass spectrometry. This should help understand how signals are propagated from the PDGF receptors, to regulate transcriptional responses and cell behavior. Last, we will identify genes that cooperate with PDGF in cancer progression, using Piggyback and Sleeping Beauty mediated transposon mutagenesis to drive gliomas in a sensitized background that already exhibits increased PDGF activity. PDGF deregulation has been implicated in the genesis of such tumors, yet PDGFR activation on its own is insufficient to drive tumor formation in mice. This study should help identify genes that work together with PDGF in neoplastic disease. Taken together these studies should help define the mechanisms by which PDGFs exert their functions during development, in the adult, and in disease. This information should be of use in preventing birth defects and in cancer therapy.
Platelet Derived Growth Factors (PDGFs) regulate the formation of many cell types during embryonic development and their maintenance in the adult, and the deregulation of the PDGF pathway has been implicated in disease and in cancer. The goal of this research is to identify genes or proteins that work together with PDGF to regulate normal physiological processes, or that are involved in cancer progression. This research should hold important benefits in treating birth defects and in cancer therapy.
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