Project Summary Of all brain cancers, glioblastoma (GBM) is the most aggressive and usually leaves patients only months to live at the time of diagnosis. GBM is characterized by a large percentage of immune cells, including central nervous system resident microglia and infiltrating bone marrow-derived macrophages. The nuclear factor- kappaB (NF-?B) signaling pathway is known to be upregulated in many types of cancer, including GBM, and research has shown that NF-?B signaling within the myeloid lineage contributes to tumor promoting properties of bone marrow-derived and tumor-associated macrophages. However, little is known about how NF-?B signaling might promote aggressive properties in microglia which could lead to GBM progression. To date, a critical barrier which has limited progress in understanding the relationship between microglial NF-?B signaling in GBM has been the lack of a suitable animal model. Our goal is to characterize an immune- competent mouse model that lacks canonical NF-?B signaling in microglia in order to investigate microglial NF- ?B signaling on GBM progression and drug resistance. Our central hypothesis is that microglial NF-?B signaling is important in driving GBM tumors. A corollary of this hypothesis is that impairing NF-?B signaling would decrease GBM development and improve therapeutic efficacy. Our objectives are (1) to characterize the animal model for use in GBM experiments; (2) to determine secretome/gene expression and impact on aggressive GBM characteristics like cancer stem cells; and (3) to determine impact of microglia-specific NF-?B deletion on tumor growth via magnetic resonance imaging, and determine tumor sensitivity to standard therapeutics.The impact will include advancing what is currently known about the relationship between NF-?B and GBM, as well as how microglia, in particular, contribute to this disease. This work could have implications in other cancer types as well, because immune cell contribution and aberrant NF-?B signaling is a hallmark of many cancers. This project will also have a direct impact on undergraduates and greatly expand research on the Summerville Campus of Augusta University, as experiments have been designed to include substantial undergraduate involvement in high caliber science. Aim 1 will test the hypothesis that NF-?B signaling in microglial is critical in promoting GBM development: Characterization of the p65fl/fl/CX3CR1creER/+ animal model. Aim 2 will test the hypothesis that NF-?B deficient microglia have altered phenotypes and can alter GBM characteristics in cell culture. Aim 3 will test the hypothesis that deficient NF-?B signaling in microglia will inhibit GBM growth in vivo and increase tumor susceptibility to therapeutics.
- National Institute of Neurological Disorders and Stroke: $443,996.00