ABSTRACT Goal: The goal of this application is to provide a structured research training program under mentors in related fields to promote the development of the applicant into an independent clinician-scientist investigating Neurofibromatosis Type II (NF2) and hearing-related disorders. The career development aims of this application are to support training in genetic and epigenetic research, incorporating important aspects of bioinformatics and biostatistics, to support the applicant’s pathway to independence. This will be accomplished through coordinated efforts in the University of Miami Department of Otolaryngology and Hussman Institute of Human Genetics (HIHG) and the Division of Neuroscience at University of Central Florida. Research Program: NF2 is a hereditary tumor disorder that predisposes children and young adults to develop multiple central nervous system tumors, particularly bilateral vestibular schwannomas (VS) that cause hearing loss (HL), imbalance, and life-threatening intracranial complications. VS occur along the cochleovestibular nerve and are caused by mutations in the NF2 tumor suppressor gene that encodes merlin protein. Although the mechanisms of tumorigenesis are known, the factors that cause tumor-mediated HL in NF2 are not well understood, thereby impeding progress in identifying effective therapies that reduce tumor burden and preserve hearing. Our interest in determining tumor-mediated mechanisms of HL has led us to the novel finding that VS demonstrate differentially methylated regions in genes of inflammatory response in patients with and without HL. Our central hypothesis is that alterations of the genomic and epigenetic profiles in VS result in aberrant changes in pro-inflammatory signaling that cause tumor-mediated HL in NF2 patients. For this work, we have developed: (1) a unique tumor bank of human VS, (2) primary human VS cell cultures, (3) an immunodeficient rat xenograft model of VS that develops HL, and (4) a clinical database. The experiments proposed here will define the role of tumor genetics and epigenetics on the expression and secretion of proinflammatory cytokines and the development of HL, which are essential steps towards establishing personalized treatments for NF2. Training Program: The applicant will participate in formal didactic lectures and hands-on training through the Master’s Program in Clinical and Translational Investigations at the University of Miami, supplementary informal didactic lectures and seminars, and one-on-one tutorials with her mentors and collaborators. She will also attend regularly scheduled intellectual activities in the Otolaryngology Department and HIHG and meet frequently with advisors to monitor her progress. Dr. Xue-Zhong Liu, Director of the Miami Otogenetic Program, and Dr. Cristina Fernandez-Valle, Professor of Neuroscience, will serve as mentors.

PROJECT NARRATIVE The relevance of this proposed project is to develop new therapies to preserve hearing in individuals with Neurofibromatosis Type II vestibular schwannomas for which there are no effective therapies. Hearing loss in Neurofibromatosis Type II affects patient safety, understanding, communication, and quality of life.