? ? Inactivation of the NF1 gene is the underlying cause for one of the most common genetic diseases of the nervous system, neurofibromatosis type 1. Neurofibromin, the gene product of NF1encodes for a 3000 amino acid protein that contains a rasGTPase activating domain (rasGAP), a negative regulator of the ras pathway. To date, prevailing evidence indicates that all pathologies associated with neurofibromatosis are the consequence of deregulation of ras signaling. The most common tumor pathologies in afflicted individuals are neurofibromas (100% incidence), malignant peripheral nerve sheath tumors (15% incidence), optic gliomas (pilocytic astrocytomas; 20% incidence), and astrocytomas (<1% incidence). We have attempted to model these tumors in mice as a means of understanding the origin, molecular details of progression, and to develop potential therapies. Initial development of mouse knockout models yielded considerable information on NF1 in development, the null phenotype resulted in embryonic lethality thus limiting our ability to examine NF1 as a tumor suppressor (Brannan et al., 1994). The genetic trick of combining germline mutations at the NF1 and p53 tumor suppressors resulted in mice that developed MPNSTs with 100% penetrance. This result provided the first indication that mutations in the mouse NF1 genes could mimic the human tumor condition effectively (Vogel et al., 1998). To achieve better control of the NF1 modeling, we have developed tissue specific mutations by use of cre/lox technology (Zhu et al., 2000). Using conditional knockouts, we have successfully modeled formation of plexiform neurofibromas, thus identifying the local cell of tumor origin and the importance of a distant partner in tumor development. Much of this application focuses on our conviction that the distant partner is a mast cell. In addition we have new models that exhibit tumors of the CNS: namely optic tract gliomas and astrocytomas. In the present application we propose to develop a greater understanding of the genesis of optic gliomas. In addition, we will interface with our colleagues Dr. Clapp and Dr. Ingram in molecular studies of mast cell contribution to neurofibroma formation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS052606-04
Application #
7482986
Study Section
Special Emphasis Panel (ZNS1-SRB-E (14))
Program Officer
Fountain, Jane W
Project Start
2005-09-20
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$1,277,420
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Bessler, Waylan K; Hudson, Farlyn Z; Zhang, Hanfang et al. (2016) Neurofibromin is a novel regulator of Ras-induced reactive oxygen species production in mice and humans. Free Radic Biol Med 97:212-222
Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z et al. (2016) Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. Hum Mol Genet 25:1129-39
Ferguson, Michael J; Rhodes, Steven D; Jiang, Li et al. (2016) Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas. Pediatr Blood Cancer 63:206-13
Stansfield, Brian K; Ingram, David A (2015) Clinical significance of monocyte heterogeneity. Clin Transl Med 4:5
Sanchez-Ortiz, Efrain; Cho, Woosung; Nazarenko, Inga et al. (2014) NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development. Genes Dev 28:2407-20
Chau, Vincent; Lim, S Kyun; Mo, Wei et al. (2014) Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors. Cancer Res 74:586-97
Li, Fang; Downing, Brandon D; Smiley, Lucy C et al. (2014) Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation 129:1213-24
Stansfield, Brian K; Bessler, Waylan K; Mali, Raghuveer et al. (2014) Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation. Am J Pathol 184:79-85
Staser, Karl; Park, Su-Jung; Rhodes, Steven D et al. (2013) Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk. J Clin Invest 123:329-34
Staser, Karl; Shew, Matthew A; Michels, Elizabeth G et al. (2013) A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp Hematol 41:56-66.e2

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