Mechanisms of Cochlear Oxidative Stress Injury and Strategies to Protect Hearing

描述（由申请人提供）：这个职业发展奖项的目标是在听觉研究方面建立一个富有成效的研究项目，这将促进我向耳鼻喉科独立临床医生兼科学家的过渡。该培训方案包括由外部咨询委员会指导的有指导的研究计划和有组织的职业发展活动。综合辅导团队包括Leonard Rybak，医学博士和博士。作为导师，维克拉姆·拉姆库马尔博士和凯瑟琳·坎贝尔博士作为共同导师。该奖项将为以患者为导向的科学研究的可持续发展奠定基础。实验工作的重点是庆大霉素（一种原型氨基糖苷）治疗后内耳氧化应激损伤的分子机制。氨基糖苷类抗生素在治疗危及生命的感染方面继续发挥着重要作用，但它们也与永久性、双侧听力丧失、平衡障碍、耳鸣和肾毒性的风险有关。作为一名耳鼻喉科医生，我关心患有各种疾病的儿童和成人，这些疾病会影响他们有效表达自己或在社会中发挥最佳作用的能力。对于那些有听力损失的病人，我

DESCRIPTION (provided by applicant): 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.