Brain tumors (astrocytomas or gliomas) represent the leading cause of cancer-related death in children and the fourth leading cause in adults. While there have been considerable advances in our ability to partially arrest their growth by targeting the genetic and molecular changes within cancer cells, a substantial number of patients with gliomas succumb to their disease, develop secondary brain dysfunction as a result of treatment, or fail to regain normal neurologic function despite treatment. We hypothesize that improved patient outcome from brain tumor treatment requires that therapies consider the bi-directional interactions between neoplastic cells and non-neoplastic cells in the tumor surround. Over the past five years, we have developed and validated several genetically-engineered mouse models (GEMMs) of low-grade glioma that recapitulate the salient features of the human condition. In this application, we will exploit these accurate GEMM systems to understand (1) the role of the tumor microenvironment, including important immune system cells, in gliomagenesis and tumor growth, (2) the effects of glioma growth on normal neuronal function, and (3) the secondary effects of chemotherapy and radiation therapy on non-neoplastic brain cells. Using a cross-disciplinary approach, we aim to unravel the cellular and molecular determinants that underlie the bi-directional interactions between neoplastic cells and non-neoplastic cells in low-grade glioma, and use these insights to identify novel strategies aimed at improving the outcome of patients with these cancers. To this end, we have assembled a new team of investigators with prior involvement in large-scale cooperative research initiatives and expertise in mouse model generation (Dr. David Gutmann), stromal interactions in brain tumors (Drs. David Gutmann, Joshua Rubin), advanced small-animal imaging (Dr. Joel Garbow), genomic influences on tumorigenesis (Dr. Karlyne Reilly), and multi-modality imaging (Dr. Mark Ellisman). Finally, we have individually leveraged the rich research environments at Washington University, University of California-San Diego, and The National Cancer Institute to tackle this complex problem in cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01CA141549-05S1
Application #
8704555
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Ogunbiyi, Peter
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-05
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$77,646
Indirect Cost
$26,563
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Diggs-Andrews, Kelly A; Brown, Jacquelyn A; Gianino, Scott M et al. (2014) Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol 75:309-16
Solga, A C; Gianino, S M; Gutmann, D H (2014) NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma. Oncogene 33:289-99
Wozniak, David F; Diggs-Andrews, Kelly A; Conyers, Sara et al. (2013) Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice. PLoS One 8:e66024
Fisher, Michael J; Avery, Robert A; Allen, Jeffrey C et al. (2013) Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology 81:S15-24
Diggs-Andrews, Kelly A; Tokuda, Kazuhiro; Izumi, Yukitoshi et al. (2013) Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann Neurol 73:309-15
O'Brien, Daniel E; Brenner, Daniel S; Gutmann, David H et al. (2013) Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1. J Pain 14:628-37
Diggs-Andrews, Kelly A; Gutmann, David H (2013) Modeling cognitive dysfunction in neurofibromatosis-1. Trends Neurosci 36:237-47
Pong, Winnie W; Higer, Samantha B; Gianino, Scott M et al. (2013) Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol 73:303-8
Brown, Jacquelyn A; Diggs-Andrews, Kelly A; Gianino, Scott M et al. (2012) Neurofibromatosis-1 heterozygosity impairs CNS neuronal morphology in a cAMP/PKA/ROCK-dependent manner. Mol Cell Neurosci 49:13-22
Simmons, Grant W; Pong, Winnie W; Emnett, Ryan J et al. (2011) Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol 70:51-62

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