Human gliomas exhibit their highest incidence between 65 and 85 years of life and hence are a disease of aging. Despite intensive effort to devise new therapies, malignant gliomas remain rapidly and uniformly fatal, particularly in the aged population. A major roadblock to improved outcome for patients with gliomas is the failure of current pre-clinical animal models, based on oncogenic paradigms applied to developing animals, to predict the efficacy of therapy in humans. Our preliminary studies demonstrated that the majority of proliferating cells in normal adult human brain and gliomas share a common glial progenitor cell (GPC) immunophenotype. Since human gliomas are a disease of aging, this finding supports the notion that aging glial progenitor cells (A-GPCs) are likely targets for human glioma formation. Of particular importance, the biological phenotype of the perinatal GPC, more commonly targeted in existing models, is distinctly different from that of the adult GPCs that persist throughout life. Therefore the GPC from aged brain is a more relevant glioma target cell to model the human disease. Despite the age-related clinical profile of human gliomas, the distinct biological phenotypes of young and aging glial progenitors and increased acquisition of genomic instability with age, the role of aging target cells in glioma formation has never been addressed. This oversight reflects, in part, the experimental challenges unique to aged neural precursor cells that are less abundant, proliferative and more prone to senescence in vitro than their young counterparts. In keeping with the intent of the R21 mechanism, this exploratory proposal involves the significant challenge of developing previously unexplored paradigms to transform aging adult GPCs (A-GPCs). Our central hypothesis is that the interactions of aging on target cells and the host brain microenvironment will recapitulate the human disease and produce distinct tumor phenotypes compared with those generated by younger targets and hosts. The objectives of this proposal are to i) compare the neoplastic vulnerability and phenotypes of transformed perinatal, young adult and aged GPCs and ii) to characterize and compare the phenotype of animal gliomas generated from these transformed GPCs in perinatal, young adult and aged brains. The significance of this collaborative project, involving experts in glioma biology, stem and progenitor cell biology and aging, will be for the first time to directly compare the impact of developmental stage and aging of both glioma target cells and host brain microenvironments on the glioma phenotype that forms in vivo. These studies will provide the basis for future R01 proposals to more comprehensively analyze the mechanism by which aging contributes to glioma phenotype and establish the relative merits of incorporating aging in pre-clinical testing of glioma therapies. ? ? ?
