Vestibular schwannomas in humans can cause morbidity associated with hearing and balance loss, facial paralysis and paresthesias, and occasionally life-threatening brainstem compression. Vestibular schwannomas can be divided into three general categories - unilateral spontaneous, neurofibromatosis type 2 (NF2) associated, and cystic-type vestibular schwannomas. Although quite distinct clinically, the source of phenotypic variation among schwannoma tumor types is currently unknown, but of great clinical interest. Furthermore, the optimal treatment regimens are not known because of a lack of understanding of fundamental tumor biology. Of the three types of tumors, NF2-associated vestibular schwannomas are the subject of the current proposal. The hallmark of NF2-associated vestibular schwannomas is bilateral tumor presentation. NF2 is historically subclassified into an aggressive and a mild form. Vestibular schwannomas are known to harbor mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene;however, not every tumor carries a mutation in the NF2-coding region. A possible role for mutation or methylation in the NF2 regulatory regions has been suggested. The long-term objective of this study is to further identify and understand factors which affect the phenotypic expression of vestibular schwannomas. The principal hypotheses of this study to be tested are that 1) transcriptional regulation plays a role in vestibular schwannoma tumorigenesis and 2) phenotypic expression is altered by specific growth signaling pathways that are deregulated in vestibular schwannomas. In support of these hypotheses, four sets of experiments are proposed.
In Specific Aim 1, they will examine the role of the regulatory region of the NF2 gene in schwannomas when mutations have not been identified in the coding region.
Specific Aim 2 will examine in transgenic mice whether RhoB is an important downstream signaling target of the NF2 protein in Schwann cells. In the third Specific Aim, they will conduct a similar transgenic analysis to over-express endoglin in Schwann cells. This will be accomplished by mating the RhoB/endoglin transgenic mice with the conditional 7Vjr2-knockout mice to determine if there is any enhancement of the phenotype.
In Specific Aim 4, they will continue to evaluate differentially expressed genes, which may influence the phenotypic expression among schwannoma tumor types. Successful completion of this study should further elucidate important pathways of vestibular schwannoma formation with good potential for future development of pharmaco-therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC005985-05S1
Application #
7850077
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
2009-07-17
Project End
2011-06-30
Budget Start
2009-07-17
Budget End
2011-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$175,500
Indirect Cost
Name
Ohio State University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Bush, Matthew L; Burns, Sarah S; Oblinger, Janet et al. (2012) Treatment of vestibular schwannoma cells with ErbB inhibitors. Otol Neurotol 33:244-57
Jacob, Abraham; Oblinger, Janet; Bush, Matthew L et al. (2012) Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas. Laryngoscope 122:174-89
Bush, Matthew L; Oblinger, Janet; Brendel, Victoria et al. (2011) AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. Neuro Oncol 13:983-99
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