Prominent biological features of normal astrocyte development include proliferation, migration and differentiation, all features recapitulated in the malignant progression of gliomas. The regulation of these processes is largely unknown although there is good evidence that Epidermal Growth Factor Receptor (EGFR) signaling may play a role in the growth and differentiation of the glial lineage. Correspondingly, EGFR also appears to be a major target in gliomagenesis where mutational activation of EGFR is associated with acquisition of the aggressive hallmarks of glioblastoma. Available evidence suggests that an immature differentiation state and INK4a deficiency act in concert to provide a permissive environment for the transforming actions of activated EGFR. My longterm goal is to understand how interactions between cellular differentiation, EGFR activation and INK4a deficiency effect the transformation of glia. My working hypothesis is that EGFR activation cooperates with INK4a deficiency in gliomagenesis and that the biological phenotype resulting from this interaction may be modulated by the cellular state of differentiation.
Specific Aim 1 : To generate and characterize a transgenic mouse that directs the expression of the tetracycline activator, rtTA, under the control of the astrocyte-specific GFAJP promoter.
Specific Aim 2 : To compare the impact of EGFR* activation on normal and INK4a deficient neural stem cells and mature astrocyte in cell culture.
Specific Aim 3 : To compare the EGFR* transcriptome in neural stem cells and mature astrocytes both wild-type or deficient for INK4a by cDNA microarray expression profiling.
Specific Aim 4 : To initiate a functional analysis of genes (identified in Specific Aim 3) whose expression is altered as a result of the state of cellular differentiation and INK4a status.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS042737-04
Application #
6827817
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2002-02-01
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
4
Fiscal Year
2005
Total Cost
$171,229
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Stegh, Alexander H; Kim, Hyunggee; Bachoo, Robert M et al. (2007) Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. Genes Dev 21:98-111
Bachoo, Robert M; Kim, Ryung S; Ligon, Keith L et al. (2004) Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci U S A 101:8384-9