| The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that functions as a molecular integrator of diverse intracellular signals that influence ribosomal biogenesis, protein translation, cell growth, and cell proliferation. The importance of the mTOR signaling pathway in nervous system function has been highlighted by the study of three distinct inherited cancer syndromes that are characterized by significant central nervous system dysfunction and the formation of astrocyte-derived brain tumors, including Lhermitte-Duclos disease (PTEN mutation), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC1 or TSC2). The genetic mutations underlying each of these disorders result in functional inactivation of proteins that negatively regulate the mTOR signaling pathway, suggesting that mTOR has a central role in both normal brain development and brain tumor formation. In these studies, I examined the role of mTOR signaling in the regulation of astrocyte growth, proliferation, and cytoskeleton organization in vitro and in vivo. I employed complementary genetic and pharmacologic approaches to study the effects of mTOR activation on primary astrocyte biology in vitro. I showed that the biologic effects mediated by mTOR are dependent on specific upstream genetic changes that promote mTOR hyperactivation. Furthermore, I identified unique downstream targets of the mTOR signaling pathway that regulate astrocyte proliferation and motility. To study the components of the mTOR signaling pathway required for astrocyte proliferation in vivo, I developed and employed several genetically-engineered mouse models. I showed that inactivation of the Pten tumor suppressor promotes high-grade glioma formation. To identify proteins involved in neurofibromatosis type 1-associated glioma formation, I employed a genetically engineered mouse model to introduce mTOR pathway genetic changes in astrocytes, allowing us to define the components of the mTOR signaling pathway that are required for astrocyte proliferation and glioma formation in vivo . Collectively, these studies demonstrate that mTOR is a central regulator of astrocyte growth, proliferation, cytoskeleton organization, and motility relevant to the pathogenesis of nervous system disorders, and suggest that therapies that target mTOR signaling may be effective treatments for brain tumors. |
