Malignant glioma affects approximately 18,000 individuals a year within the US. The mortality of this disease remains largely unchanged over the past 40 years with majority of patients surviving only 12-18 months after diagnosis. The disease is characterized clinically with unrestrained proliferation, normal tissue invasion, and abnormal vascularization. As the disease progresses, the neurologic cost to patients is unmatched by any other form of cancer and few neurologic diseases. Current therapies, which rely on surgery and radiation, address only proliferation and have little impact on the other behaviors of this cancer. We propose to expand upon our understanding of the glioma phenotype by advancing our research on the impact of post-transcriptional regulation. The current proposal will build upon our observations that the RNA-binding protein, HuR, is overexpressed by malignant glioma and that in a microenvironment of central nervous system neoplastic conversion, post-transcriptional regulation has a major influence on expression of VEGF, IL-8, and TNF-a. The current objectives will advance our understanding of this impact at the subcellular, cellular, and tissue levels. The subcellular approach will focus on the process that regulates the phosphorylation of HuR and the interactions with other proteins as well as cellular localization. To move to the cellular level, we will focus on the effect of HuR """"""""knockdown"""""""" and dominant-negative mutants on glioma survival/proliferation and tumor-induced angiogenesis. At the tissue level, we have proposed to use novel assays to quantitate tumor progression and angiogenesis both at the histologic level and with non-invasive perfusion imaging. The proposed area of research is a novel aspect of cancer control that will complement and build upon the current advances in cancer signaling. ? ?
