The purpose of this project will be to model NF1 syndrome associated glial malignancies using a novel system for random, transposon-based, somatic insertional mutagenesis developed in the Largaespada laboratory. The development of malignancy is a serious and feared aspect of NF1 syndrome. Little is known about germline alterations that could predispose some NF1 patients to these malignancies. While some insight has been gained in the somatic changes that can occur in NF1 syndrome-associated malignant tumors, it is likely that much remains to be learned. An unbiased screen for somatic mutations that could accelerate malignancy after NF1 gene loss in a model could provide a list of candidate genes to examine for alterations in human NF1-associated malignancies and genes that could influence germline susceptibility. The Largaespada lab has developed a system for random, transposon-based somatic mutagenesis that can be used in forward genetic screens for cancer genes in mice. The system uses the Sleeping Beauty (SB) transposon, which is a synthetic, Tc1/mariner family transposon derived from Salmonid fish. This system was used to accelerate sarcoma development in p19Arf-/- mice and, after some modification, to induce lymphoma, medulloblastoma, and astrocytoma in wild-type mice. In this proposal SB-based somatic mutagenesis will be applied to Schwann cells in the context of a wild type background, loss of the Nf1 gene or EGFR overexpression in mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS057531-05
Application #
8382453
Study Section
Special Emphasis Panel (ZNS1-SRB-G)
Project Start
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$278,333
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Jousma, Edwin; Rizvi, Tilat A; Wu, Jianqiang et al. (2015) Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. Pediatr Blood Cancer 62:1709-16
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Brundage, M E; Tandon, P; Eaves, D W et al. (2014) MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1. Oncogene 33:5626-36
Wu, J; Patmore, D M; Jousma, E et al. (2014) EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene 33:173-80
Watson, Adrienne L; Anderson, Leah K; Greeley, Andrew D et al. (2014) Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity. Oncotarget 5:1502-14
Prada, Carlos E; Jousma, Edwin; Rizvi, Tilat A et al. (2013) Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol 125:159-68
Rahrmann, Eric P; Watson, Adrienne L; Keng, Vincent W et al. (2013) Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nat Genet 45:756-66
Largaespada, David; Ratner, Nancy (2013) Interweaving the strands: ýý-catenin, an HIV co-receptor, and Schwann cell tumors. Cancer Cell 23:269-71

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