This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder in which patients often develop multiple lesions, including slow growing spinal cord schwannomas and cutaneous schwannomas in the periphery, and meningiomas and gliomas in the brain and spine. Although usually benign and focal schwannomas and meningiomas associated with NF2 can severely compromise neural function leading to paralysis, deafness, and death through compression of critical brain nerves and structures, or blockade of CSF flow. In NF2, the most severe and life-threatening tumors are cranial nerve schwannomas and meningiomas at the skull base, which due to their size or multiplicity, are not surgically accessible. Repeated resection of tumor material can leave patients with multiple neurologic deficits, further loss of nerve function, and so debilitated that further surgery is not helpful. Thus, it is our hope to find a novel pharmacological drug which effectively reduces tumor growth as an alternative to surgery. NF2 is caused primarily by dysfunction of the NF2 gene product called merlin which inhibits directly PAK1, a Rac/ CDC42-dependent Ser/Thr kinase. In collaboration with Dr. Hiroshi Maruta at the Hamburg University Hospital (UKE) in Germany, we are screening a number of pharmacological inhibitors of PAK1 in a murine xenograft model for NF2. Tumors are formed from subcutaneous implantation of a schwannoma cell line into the flanks of immunodeficient mice. It is our objective to find a PAK1 inhibitor which reduces the growth of schwannomas in our NF2 mouse model. This drug(s) will have tremendous clinical implications for the future, particularly if it could be used in place of invasive surgery, which often leaves patients debilitated. The resources of NCRR BRC used for this project include the tissue culture room, laboratory, and office space. Funding for this project include the NF CURE award to S. M. M. from NF CURE JAPAN, and a grant from the Peterson Foundation to support the research of S. M. M. This work was presented at the NF Conference sponsored by the Children's Tumor Foundation in June, 2007 in Park City, Utah.
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