Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome resulting from loss of function mutations in the Nf2 gene locus, which codes for the protein, Merlin (Moesin-Ezrin- Radixin-Like Protein). Patients with NF2 suffer almost invariably from bilateral vestibular schwannomas (VS) and have a high propensity for sensorineural hearing loss, vestibular dysfunction, and the development of meningiomas and ependymomas. Surgical resection is currently frontline therapy for the treatment of VS and the necessity for surgical margins can further compromise auditory, vestibular, and facial nerve function. Merlin has an actin binding domain and localizes to the cortical membrane in the cell where it is believed to function as a negative regulator of cell growth during contact inhibition. In order to develop a better understanding of how loss of Merlin contributes to schwannoma genesis, the lab generated a murine model of NF2 in which Nf2flox/flox mice have been crossed with mice which express Cre recombinase driven by a 3.9kb fragment of the periostin (Postn) promoter. These Nf2f/f;Postn-Cre mice develop a clinical pathology similar to human NF2 patients with fully penetrant peripheral, vestibular, and dermal schwannomas along with sensorineural hearing loss. We hypothesize that loss of Merlin drives oncogenic transformation of Schwann cells through up- regulation of the NF-?B pathway.
In Aim 1, we will develop new tools to elucidate NF-kB signaling in our NF2 mouse model. By modulating the signaling of a specific NF-?B protein, we will attempt to prevent pathogenic schwannoma formation in our Merlin conditionally deficient animals and assess how tumor growth alters the sensorineural hearing loss.
In Aim 2, we seek to modulate a therapeutically targetable protein as a way of ameliorating a particular disease process we have observed in the inner ear of our mice and that we hypothesize is primary driver of hearing loss in our mice. The studies in Aim 1 and 2 are designed to challenge the prevailing opinion about the pathophysiology driving sensorineural hearing loss in NF2. This proposal will lead to a better understanding of Merlin signaling and provide a data driven approach to how to think about and treat sensorineural hearing loss in NF2.
Neurofibromatosis Type 2 (NF2) is a genetic condition which predisposes individuals to sensorineural hearing loss and Schwann cell tumors. Using a murine model of NF2, we will define the cell signaling aberrations responsible for hearing loss and tumor development and challenge prevailing opinions surrounding the pathophysiology of hearing loss in NF2. We will advance a therapeutically targetable protein as a novel drug target for the prevention of tumor formation and hearing loss in NF2.
| Gehlhausen, Jeffrey R; Hawley, Eric; Wahle, Benjamin Mark et al. (2018) A proteasome-resistant fragment of NIK mediates oncogenic NF-?B signaling in schwannomas. Hum Mol Genet : |
