The goal of this career development award is to establish a productive research program in auditory research that will foster my transition to an independent clinician-scientist in otolaryngology. This training program comprises a mentored research plan with guidance by an external advisory committee and structured career-enhancing activities. The integrated mentoring team includes Leonard Rybak, M.D.,Ph.D. as mentor and Vickram Ramkumar, Ph.D., and Kathleen Campbell, Ph.D. as co-mentors. This award will lay the groundwork for a sustainable career in patient-directed scientific investigation The experimental work focuses on the molecular mechanisms responsible for oxidative stress injury to the inner ear after treatment with gentamicin, a prototype aminoglycoside. Aminoglycoside antibiotics continue to have an essential role in the treatment of life-threatening infections, but they are also associated with a risk of permanent, bilateral hearing loss, as well as balance disturbance, tinnitus, and nephrotoxicity. As an otolaryngologist, I care for children and adults suffering from a broad range of disorders that affect their ability to express themselves effectively or to function optimally in society. For those patients with hearing loss, I can see the far-reaching effects of impaired communication on their lives. My longstanding commitment to taking findings in the laboratory and bringing them to the bedside provides the impetus for this translational research program. The research strategy emphasizes the role of oxidative stress based on prior studies showing that reactive oxygen species contribute to drug-induced and noise-induced hearing loss and that dampening these reactive oxygen species may confer otoprotection. Different types of insults to the ear may converge on common molecular pathways to cause cochlear inflammation and ultimately hair cell death. The central hypothesis of this research plan is that targeted interference with oxidative stress can attenuate cochlear inflammation and in doing so decrease the risk of gentamicin-induced injury to the inner ear. Use of a targeted approach may also decrease the risk of serious side effects. The five-year research plan involves a series of related experiments that investigate the mechanisms of gentamicin ototoxicity and the role of transplatin as a potential otoprotectant. Transplatin is an inactive trans-isomer of cisplatin that reduces expression of several key molecules involved in drug-induced hearing loss. A dose-response effect for transplatin protection will be determined in an animal model by delivering transplatin via transtympanic or systemic routes. Assessments will be made by scanning electron microscopy, auditory brainstem response testing, and immunohistochemical assays. Experiments in cochlea-derived cell lines will investigate how transplatin modulates oxidative stress, gene expression, and inflammation in the cochlea. This work will better define the role of cell membrane channels, transcription factors, and other molecular targets in gentamicin-induced hearing loss. The long-term goal of this research is to develop safe and effective strategies to prevent hearing loss related to aminoglycoside antibiotic therapy.
Aminoglycoside antibiotics have an essential role in treatment of life-threatening neonatal sepsis and are part of the treatment regimen for multidrug-resistant tuberculosis recommended by the World Health Organization, but aminoglycoside therapy has significant risks of hearing loss, balance impairment, and nephrotoxicity. Aminoglycosides are administered frequently in neonatal intensive care units in the United States, and the incidence of gentamicin-induced hearing loss is estimated at 8 percent following a limited duration of treatment. Children are particularly susceptible to hearing loss, with even mild hearing impairment during their early years hampering speech, cognition, and social development, and the projected cost of the therapy, education, and rehabilitation for each child who suffers from hearing loss has been estimated to be at least $417,000.
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