The objective of this application is to identify the role of p21-Activated Kinase 1 (Pak1) in molecular pathways responsible for specific cellular and biochemical phenotypes associated with plexiform neurofibroma formation resulting from the genetic disorder Neurofibromatosis Type I (NF1). Neurofibromatosis is the result of mutations at the NF1 locus, which encodes the large GTPase activating protein neurofibromin. Neurofibromin is a negative regulator of the proto-oncogene p21Ras(Ras). Ras hyperactivation is the molecular basis of NF1 associated phenotypes, and our group has demonstrated that restoration of Ras signaling to wild type levels can correct NF1 associated phenotypes in vitro and in vivo. NF1 is a common, pandemic, inherited disease that affects over 200,000 patients in North America, Europe, and Japan alone. Individuals with NF1 display a wide variety of pathologies;importantly, 15-40% of NF1 patients are affected by plexiform neurofibromas. Neurofibromas are complex tumors consisting of tumorgenic Schwann cells surrounded by endothelial cells, fibroblasts, and inflammatory mast cells. Recent evidence from our group indicates that the hematopoietic tumor microenvironment carries out a crucial function in the formation of plexiform neurofibromas. These tumors affect the peripheral nerves and commonly can be found in the face, limbs, or along the spinal nerve roots. These lesions contribute significantly to the morbidity and mortality associated with NF1. Currently, no medical therapies exist for treating neurofibromas. In keeping with our long term goal of detecting potential molecular targets for medical therapies to treat human plexiform neurofibromas, we have identified the kinase Pak1 as a possible downstream intermediary of Ras signaling in NF1 deficient cells. Therefore, by intercrossing mice heterozygous at Nf1 (the murine homolog of NF1) with Pak1-/- mice, we are able to test genetically, in vitro and in vivo, the hypothesis that inactivation of Pak1 would lead to correction of the gains of function phenotypes seen in Nf1 haploinsufficient cells. Further, we will determine the role of Pak1 in the development of neurofibromas, by utilizing a conditional Nf1 knockout mouse (Krox20Cre;Nf1flox/-) that is a reliable model of plexiform neurofibroma formation. These studies will provide insight into the causes of debilitating tumors related to a common genetic disease. No treatment for these tumors exists at this time, and this research could potentially lead to the development of medical therapies for these tumors. Preventing or reducing the size of these tumors could increase quality of life for tens of thousands of affected individuals each year.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS060322-03
Application #
7682910
Study Section
Special Emphasis Panel (ZNS1-SRB-M (47))
Program Officer
Fountain, Jane W
Project Start
2007-09-07
Project End
2010-08-31
Budget Start
2009-09-07
Budget End
2010-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$34,201
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Butler, Randall T; Spector, Matthew E; Thomas, Dafydd et al. (2014) An immunohistochemical panel for reliable differentiation of salivary duct carcinoma and mucoepidermoid carcinoma. Head Neck Pathol 8:133-40
McDaniel, Andrew S; Allen, Jayme D; Park, Su-Jung et al. (2008) Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/- mast cells. Blood 112:4646-54