Novel Mechanisms Regulating Cytokine-induced Gene Expression in Astrocytes and Glioblastoma Cells

NOVEL MECHANISMS REGULATING CYTOKINE-INDUCED GENE EXPRESSION IN ASTROCYTES AND GLIOBLASTOMA CELLS By Lauren Elizabeth Bryan, Ph.D. A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctorate of Philosophy in Biochemistry and Molecular Biology at Virginia Commonwealth University. Virginia Commonwealth University, 2009 Major Director: Tomasz Kordula, Ph.D. Associate Professor, Department of Biochemistry and Molecular Biology Chronic inflammation in the brain results in the development of several CNS diseases, including Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and tumors. IL-1, a pro-inflammatory cytokine released by activated microglia and astrocytes, instigates the expression of factors promoting the progression of these CNS disorders, including cytokines, chemokines, and components of matrix remodeling systems, such as the plasminogen activator system. IL-1 also increases the mRNA expression and activity of SphK, the enzyme that phosphorylates Sph to form S1P, a bio-active sphingolipid. This