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Danielle Sandsmark
Hometown: Belvidere, IL
Undergrad: Coe College (2001)
Program of Study: Neurosciences
Thesis Lab: Dr. David Gutmann
Short Description: Dissection of the mTOR signaling pathway in astrocytes
Email: sandsmarkd@msnotes.wustl.edu
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RESEARCH
"Dissection of the mTOR Signaling Pathway in Astrocytes"
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 (TSCI 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 defme 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.
GRADUATE PUBLICATIONS
Sandsmark DK, Pelletier C, Weber JD, Gutmann DH. Mammalian target of rapamycin: master regulator of cell growth in the nervous system. Histol Histopathol. 2007 Aug;22(8):895-903.
Sandsmark DK, Zhang H, Hegedus B, Pelletier CL, Weber JD, Gutmann DH. Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-defecient astrocytes. Cancer Res. 2007 May 15;67(10):4790-9.
Wei Q, Clarke L, Scheidenhelm DK, Qian B, Tong A, Sabha N, Karim Z, Bock NA, Reti R, Swoboda R, Purev E, Lavoie JF, Bajenaru ML, Shannon P, Herlyn D, Kaplan D, Henkelman RM, Gutmann DH, Guha A. High-grade glioma formation results from postnatal pten loss or mutant epidermal growth factor receptor expression in a transgenic mouse glioma model. Cancer Res. 2006 Aug 1;66(15):7429-37.
Scheidenhelm DK, Cresswell J, Haipek CA, Fleming TP, Mercer RW, Gutmann DH. Akt-dependent cell size regulation by the adhesion molecule on glia occurs independently of phosphatidylinositol 3-kinase and Rheb signaling. Mol Cell Biol. 2005 Apr;25(8):3151-62.
Scheidenhelm DK, Gutmann DH. Mouse models of tuberous sclerosis complex. J Child Neurol. 2004 Sep;19(9):726-33.
Uhlmann EJ, Li W, Scheidenhelm DK, Gau CL, Tamanoi F, Gutmann DH. Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation. Glia. 2004 Aug 1;47(2):180-8.
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