Mechanisms of Cochlear Oxidative Stress Injury and Strategies to Protect Hearing

耳蜗氧化应激损伤机制及听力保护策略

• 批准号: 8911694
• 负责人: Michael J. Brenner
• 金额: $ 22.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911694
• 关键词: Adult; Adverse effects; Advisory Committees; Affect; Aftercare; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Antibiotic Therapy; Apoptotic; Attenuated; Auditory; Auditory Brainstem Responses; Auditory Evoked Potentials; Award; Bilateral Hearing Loss; Biochemical; Biochemical Pathway; Biological Assay; Cations; Cell Death; Cell Line; Cell membrane; Cells; Child; Child Care; Cisplatin; Clinical; Cochlea; Cognition; Communication; Data; Disease; Doctor of Medicine; Doctor of Philosophy; Dose; Down-Regulation; Dyes; Ear; Education; Epigenetic Process; Equilibrium; Etanercept; Event; Fostering; Free Radicals; Funding; Future; Gene Expression; Generations; Genes; Gentamicins; Goals; Hair Cells; Hearing; Hemorrhage; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Injury; Intervention; Investigation; Ion Channel; Isomerism; K-Series Research Career Programs; Kidney; Knowledge; Laboratories; Labyrinth; Life; Measures; Mediating; Mediator of activation protein; Mentors; Molecular; Molecular Target; Multidrug-Resistant Tuberculosis; Mus; NADPH Oxidase; Neonatal Intensive Care Units; Neoplasms; Noise-Induced Hearing Loss; Organ of Corti; Otolaryngologist; Otolaryngology; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Preventive; Protein Isoforms; Proteins; Rattus; Reactive Oxygen Species; Rehabilitation therapy; Research; Risk; Role; Route; STAT protein; STAT1 gene; Scanning Electron Microscopy; Scientist; Series; Small Interfering RNA; Social Development; Societies; Speech; Stress; Structure; Testing; Texas red; Time; Tinnitus; Toxic effect; Training Programs; Translational Research; Translations; Treatment Protocols; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; United States; Vanilloid; Work; World Health Organization; aminoglycoside-induced ototoxicity; antimicrobial; base; career; career development; cost; cyclooxygenase 2; effective therapy; equilibration disorder; hearing impairment; human NOS2A protein; immortalized cell; in vivo; inner ear injury; intraperitoneal; neonatal sepsis; nephrotoxicity; ototoxicity; prevent; programs; prototype; receptor; regenerative; research study; response; therapeutic target; transcription factor; transplatin; treatment duration; uptake

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.

描述（由申请人提供）：该职业发展奖的目标是在听觉研究中建立一项生产研究计划，该计划将促进我向耳鼻喉科独立临床医生的过渡。该培训计划包括一项指导的研究计划，并在外部咨询委员会和结构化职业增强活动的指导下进行了指导。综合指导团队包括医学博士Leonard Rybak。作为Mentor和Vickram Ramkumar博士，以及凯瑟琳·坎贝尔（Kathleen Campbell）博士。作为联合官员。该奖项将为患者指导的科学研究的可持续职业奠定基础。实验工作重点介绍了用甲状腺素（一种原型氨基糖苷）治疗庆大霉素后，导致内耳氧化应激损伤的分子机制。 氨基糖苷抗生素在威胁生命的感染中继续起着至关重要的作用，但它们也与永久性，双侧听力损失以及平衡障碍，耳鸣和肾毒性的风险有关。作为耳鼻喉科医生，我照顾患有各种疾病的儿童和成年人，这些疾病会影响他们有效表达自己或在社会中发挥最佳功能的能力。对于那些听力损失的患者，我 可以看到沟通受损对他们生活的深远影响。我长期致力于在实验室中进行调查并将其带到床边，这为这项翻译研究计划提供了动力。该研究策略强调了基于先前的研究，强调氧化应激的作用，表明活性氧促进了药物诱导的和噪声诱导的听力损失，并且抑制这些活性氧气可能会赋予局限性。对耳朵的不同类型的侮辱可能会在常见的分子途径上汇聚，以引起耳蜗炎症并最终导致毛细胞死亡。该研究计划的核心假设是，针对氧化应激的有针对性干扰会减轻耳蜗炎症，并在这样做会降低庆大霉素引起的内耳损伤的风险。使用目标方法也可能降低严重副作用的风险。五年的研究计划涉及一系列相关的实验，这些实验研究了庆大霉素耳毒性的机制以及移植蛋白作为潜在的治疗剂的作用。移植蛋白是顺铂的一种无活跃的反异构体，可降低与药物诱导的听力丧失有关的几个关键分子的表达。通过跨抑制或全身途径传递移植蛋白，将在动物模型中确定用于移植蛋白保护的剂量反应效应。评估将通过扫描电子显微镜，听觉脑干反应测试和免疫组织化学测定进行评估。耳蜗衍生细胞系中的实验将研究移植素如何调节耳蜗中的氧化应激，基因表达和炎症。这项工作将更好地定义细胞膜通道，转录因子和其他分子靶标在庆大霉素引起的听力损失中的作用。这项研究的长期目标是制定安全有效的策略，以防止与氨基糖苷抗生素疗法有关的听力损失。