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.