Patients with neurofibromatosis type 1 (NF1) develop benign peripheral nerve sheath tumors called neurotlbromas. Within neurofibromas, biallelic mutations in the NF1 gene are found in tumor Schwann cells, indicating that tumorigenesis requires complete loss of function at NF1 in tumor Schwann cells. Malignant progression of neurofibromas to malignant peripheral nerve sheath tumors occurs in about 10% of NF1 patients. No therapies currently exist for neurofibroma or MPNST. The NF1 protein, neurofibromin, is a GTPase-activating protein (GAP) for Ras proteins, molecular switches that control multiple signaling cascades. Loss of neurofibromin leads to increased levels of Ras-GTP in Schwann cells. We used in vitro model systems for Schwann cell tumorigenesis in NF1 to clarify signaling pathways underlying tumorigenesis. Surprisingly, we found that increased migration and cAMP accumulation in Nf1 mutant Schwann cells was not accounted for by Ha-Ras-GTP. Rather, these phenotypes may require the related and little studied Ras protein TC21/R-Ras2. TC21 uses downstream effectors differently from other Ras proteins. We propose to critically evaluate the relevance of TC21 to formation of neurofibroma and MPNST. Specifically, in Aims 1 &2 we will define cellular and molecular effects of TC21 in Nf1 mutant Schwann cells, and human MPNST xenografts.
In Aim 3 we will use mouse models to test whether loss of TC21 delays or blocks neurofibroma or MPNST formation Together these studies are anticipated to identify novel intervention points at which to treat human NF1 disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS057531-05
Application #
8382450
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
$292,295
Indirect Cost
$93,913
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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