Funded Grants

Generation of a YAC transgenic mouse model to study the role of PDGFRA in brain tumor development

The PDGFRa is the universal receptor for PDGF (platelet-derived growth factor), and activation of this receptor leads to a wide range of biological actions. Accumulating evidence has indicated that the PDGFRa plays an important role in embryonic development, and aberrant expression of this receptor is thought to play a role in the development of a subclass of brain tumors. Here we wish to establish an in vivo model to study the regulatory mechanisms involved in the expression of the PDGFRA. For this purpose we will create transgenic mice with YACs (yeast artificial chromosomes), carrying the complete PDGFRa gene. Manipulation of these YACs by homologous recombination in yeast, and the subsequent introduction of the mutated YACs into mice, will enable us to map the regulatory elements involved in the correct expression of PDGFRA in various tissues. This information will then be used to search for possible regulatory defects associated with brain tumor formation and leading to the improper expression of the PDGFRa. In addition, we will use the isolated elements of the PDGFRA promoter to specifically target putative glioma precursor cells, of which a large fraction is thought to be PDGFRa positive. This will be done in "classical" transgenic mouse models, where the role of different growth and survival factors (particularly PDGF) in the development of brain tumors is our focus. There are presently no promoters available for directing specific gene expression to relevant oligodendroglial precursors.This work may lead to the establishment of a very powerful in vivo model system to study various aspects of PDGF action, in particular with respect to its involvement in the generation of brain tumors. Understanding the growth regulatory defects of human gliomas is of great importance since no effective treatment exists at present for this type of tumor. The use of the relatively new YAC transgenic technique will also not be restricted to the described project, but it can, and will have a much wider application within the field of cancer research.