Targeting Inflammation for the Amelioration of Cisplatin-Hearing Loss

针对炎症改善顺铂听力损失

• 批准号: 8180477
• 负责人: Vickram Ramkumar
• 金额: $ 43.65万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-04 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8180477
• 关键词: Adrenal Cortex Hormones; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Attenuated; Bilateral; Cancer Patient; Carboplatin; Caspase; Cell Death; Cells; Cellular Membrane; Cessation of life; Childhood; Cisplatin; Clinical; Cochlea; Cognition; Communication; DNA Repair Enzymes; Data; Development; Enzymes; Etanercept; Future; Generations; Genes; Goals; Hair Cells; Head and Neck Neoplasms; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Laboratories; Labyrinth; Lead; Link; Lipid Peroxidation; Malignant Neoplasms; Mediating; Mediation; Molecular Profiling; NADPH Oxidase; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Nuclear; Organ of Corti; Outer Hair Cells; Patients; Pharmaceutical Preparations; Phosphorylation; Platinum; Population; Process; Protein Isoforms; Proteins; RNA; Reactive Oxygen Species; Records; Regimen; Research; Research Proposals; Role; STAT protein; Sensorineural Hearing Loss; Signal Transduction; Signaling Molecule; Small Interfering RNA; Social Development; Social skills development; Solid Neoplasm; Source; Speech; System; TNF gene; TRPV1 gene; Testing; Therapeutic; Transcription Coactivator; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Tympanic membrane; Vanilloid; base; chemotherapeutic agent; chemotherapy; combat; cyclooxygenase 2; cytokine; effective therapy; hearing impairment; human NOS2A protein; inhibitor/antagonist; nephrotoxicity; novel; novel strategies; ototoxicity; oxaliplatin; receptor; sound; transcription factor; transmission process; treatment strategy; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Ototoxicity is a common side effect of cisplatin, a drug widely used for the treatment of a various solid tumor. Cisplatin ototoxicity is irreversible and is especially traumatic for the pediatric population since it hampers their communication skills and social development. Cisplatin is unique among platinum-based chemotherapy by having a broad spectrum of activity against a number of different cancers compared to more limited activity for carboplatin and oxaliplatin. The continued clinical use of cisplatin suggests ototoxicity will continue to be a problem unless a substantial effort is undertaken to develop effective otoprotective therapies. One current treatment strategy uses antioxidants to decrease reactive oxygen species (ROS), which has been implicated in cisplatin ototoxicity. While this approach provides otoprotection, there are concerns that antioxidants could limit the efficacy of cisplatin. Other treatment approaches target proteins involved in apoptosis which contribute to death of outer hair cells (OHCs). However, inhibition of caspases, p53, or activation of DNA repair enzymes may promote the development of tumors or promote tumor chemoresistance. A more rational approach should target the source of ROS generation or downstream signaling molecules which are not linked to oncogenesis and utilize localize (intra-tympanic) delivery of otoprotective agents. We have identified two such molecules, namely the NADPH oxidase isoform, NOX3 (a major source of ROS generation in the cochlea) and transient receptor potential vanilloid 1 channel (implicated in cisplatin ototoxicity). Knockdown of these proteins reduced damage to OHCs and reduced hearing loss induced by cisplatin. Recent findings from our laboratories indicate that TRPV1 and NOX3 can increase the activity of signal transducers and activators of transcription (STAT1), an important mediator of inflammation. Knockdown of STAT1 reduced the expression of inflammatory genes (such as TNF-a) and protected against cisplatin-induced hearing loss. This has led to the hypothesis that inflammation is a significant component of cisplatin-induced ototoxicity. Furthermore, we proposed that STAT1 is a downstream target of NOX3 and TRPV1 and thereby represents a novel target for otoprotective drugs. The overall goal of this project is to examine a role of STAT1 in cisplatin ototoxicity and determine whether it represents a viable target for otoprotective therapies. Specifically, we will (1) determine the mechanism(s) underlying ROS activation of STAT1, (2) characterize in more detail the ability of intra-tympanic injection of STAT1 siRNA to inhibit cisplatin-induced hearing loss, (3) determine the expression profile of inflammatory genes induced by cisplatin and (4) to determine whether intra-tympanic injection of a selective inhibitor of TNF-a (etanercept) protects against cisplatin ototoxicity. Overall, the data obtained from this study would expand our understanding of STAT1 activation in the cochlea and provide the rationale for targeting this transcription factor for combating cisplatin ototoxicity and other forms of hearing loss. Our findings are expected to have direct translational application to the treatment of hearing loss in cancer patients. PUBLIC HEALTH RELEVANCE: The current research proposal focuses on hearing loss observed clinically in patients being treated with the anticancer drug, cisplatin. Research from our laboratory indicates that cisplatin produces inflammation in the inner ear and this leads to death of cells responsible for transmission of sound in the inner ear. We will test the ability of anti-inflammatory agents to protect against cisplatin-mediated hearing loss when administered directly through the ear drum. We believe the information gained from this study will lead to potentially new treatments for treating hearing loss.

描述（由申请人提供）： 耳毒性是顺铂的常见副作用，顺铂是一种广泛用于治疗各种实体瘤的药物。顺铂耳毒性是不可逆的，对儿科人群尤其造成伤害，因为它会妨碍他们的沟通技巧和社会发展。顺铂在铂类化疗中是独一无二的，与卡铂和奥沙利铂的活性有限相比，顺铂对多种不同的癌症具有广泛的活性。顺铂的持续临床使用表明，除非付出巨大努力来开发有效的耳保护疗法，否则耳毒性将继续成为一个问题。目前的一种治疗策略是使用抗氧化剂来减少活性氧 (ROS)，活性氧与顺铂耳毒性有关。虽然这种方法提供了耳保护，但有人担心抗氧化剂可能会限制顺铂的功效。其他治疗方法针对参与细胞凋亡的蛋白质，这些蛋白质导致外毛细胞 (OHC) 死亡。然而，抑制caspases、p53或激活DNA修复酶可能会促进肿瘤的发展或促进肿瘤化疗耐药。更合理的方法应该针对 ROS 生成源或与肿瘤发生无关的下游信号分子，并利用耳保护剂的局部（鼓室内）递送。我们已经鉴定了两种这样的分子，即 NADPH 氧化酶同工型、NOX3（耳蜗中 ROS 生成的主要来源）和瞬时受体电位香草酸 1 通道（与顺铂耳毒性有关）。这些蛋白质的敲低减少了对 OHC 的损害，并减少了顺铂引起的听力损失。我们实验室的最新研究结果表明，TRPV1 和 NOX3 可以增加信号转导子和转录激活子 (STAT1) 的活性，STAT1 是炎症的重要介质。 STAT1 的敲低可减少炎症基因（如 TNF-a）的表达，并防止顺铂引起的听力损失。这导致了这样的假设：炎症是顺铂引起的耳毒性的重要组成部分。此外，我们提出 STAT1 是 NOX3 和 TRPV1 的下游靶点，因此代表了耳保护药物的新靶点。该项目的总体目标是检查 STAT1 在顺铂耳毒性中的作用，并确定它是否代表耳保护疗法的可行靶点。具体来说，我们将 (1) 确定 STAT1 ROS 激活的机制，(2) 更详细地表征鼓室内注射 STAT1 siRNA 抑制顺铂诱导的听力损失的能力，(3) 确定顺铂诱导的炎症基因的表达谱，以及 (4) 确定是否鼓室内注射选择性 TNF-a 抑制剂 （依那西普）可防止顺铂耳毒性。总的来说，从这项研究中获得的数据将扩大我们对耳蜗中 STAT1 激活的理解，并为针对该转录因子对抗顺铂耳毒性和其他形式的听力损失提供理论依据。我们的研究结果预计将直接转化应用于癌症患者听力损失的治疗。 公共健康相关性：当前的研究计划重点关注接受抗癌药物顺铂治疗的患者中临床观察到的听力损失。我们实验室的研究表明，顺铂会引起内耳炎症，从而导致负责内耳声音传输的细胞死亡。我们将测试直接通过耳膜给药时抗炎药预防顺铂介导的听力损失的能力。我们相信从这项研究中获得的信息将带来治疗听力损失的潜在新疗法。