Role of P53 in Aminoglycoside Ototoxicity

P53 在氨基糖苷类耳毒性中的作用

• 批准号: 7559968
• 负责人: MEI ZHANG
• 金额: $ 7.93万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-06 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559968
• 关键词: Address; Adverse effects; Affect; American; Antioxidants; Apoptosis; Apoptotic; Caspase Inhibitor; Cell Death; Cells; Cellular biology; Cisplatin; Clinic; DNA-dependent protein kinase; Data; Dizziness; Dose; Environment; Epithelium; Event; Future; Generations; Gentamicins; Goals; Hair Cells; In Vitro; Injection of therapeutic agent; Labyrinth; Left; MAPK8 gene; Manuscripts; Maps; Meniere' s Disease; Methionine; Methods; Modeling; Molecular; Organ of Corti; Outcome; Outcome Study; Pathway interactions; Pharmaceutical Preparations; Principal Investigator; Process; Rattus; Reactive Oxygen Species; Research; Role; Sensory; Serine; Signal Pathway; Stimulus; TP53 gene; Time; Tinnitus; Toxic effect; Type II Hair Cell; Utricle structure; Vestibular Hair Cells; Western Blotting; Work; accomplished suicide; aminoglycoside-induced ototoxicity; base; cell injury; clinical application; drug mechanism; ebselen; hearing impairment; in vitro Model; in vivo; inhibitor/antagonist; ototoxicity; pifithrin; postnatal; prevent; programs; protective effect; research study; response; salicylate; theories

DESCRIPTION (provided by applicant): Twenty eight million Americans suffer from hearing loss. Hair cell loss induced by ototoxic drugs, such as cisplatin and gentamicin, are among the most common causes of hearing loss, dizziness and tinnitus. Clinically, no drug is available to treat the hair cell loss. Therefore, the long-term goal of our study is to understand the mechanism of hair cell death and develop drugs to prevent and treat hair cell loss. P53 is a key regulator in apoptotic process. We discovered that pifithrin-a (PFT), an inhibitor of p53, blocked cisplatin induced apoptosis and protected hair cells in the cochlear and vestibular cultures. In addition, our data showed PFT also prevented gentamicin-induced hair cell death. Thus, PFT is a potential molecule to treat drugs-induced ototoxicity. Moreover, our data showed that PFT significantly protects the cochlear hair cells but not the vestibular hair cells against low dose gentamicin. Intratympanic injection of low dose gentamicin to damage the vestibular hair cells has been widely used to treat the dizziness of Meniere's disease. However, gentamicin induced hearing loss due to cochlear hair cell damage is the major concern. In this circumstance, PFT has great potential clinical application. In this project, we will study the PFT protective mechanism. In addition, we will delineate p53 upstream and downstream signaling pathways, which will draw a map with specific targets for future protection against cisplatin and gentamicin ototoxicity. We will use organotypic cultures of organ of Corti and utricle of postnatal rats, which are well-established models to study ototoxicity. The outcome of the study will have clinical application toward developing new therapies to protect against drug-induced ototoxicity and will contribute to the understanding of the molecular mechanisms of drug-induced ototoxicity.

描述（由申请人提供）：2800万美国人因听力损失而遭受。耳毒性药物诱导的毛细胞损失，例如顺铂和庆大霉素，是听力丧失，头晕和耳鸣的最常见原因之一。临床上，没有药物可用于治疗毛细胞损失。因此，我们研究的长期目标是了解毛细胞死亡的机理，并开发药物以预防和治疗毛细胞损失。 p53是凋亡过程中的关键调节剂。我们发现，p53的抑制剂pifithrin-a（PFT）阻断了顺铂诱导的细胞凋亡，并在人工耳蜗和前庭培养物中受保护的毛细胞。此外，我们的数据显示PFT还阻止了庆大霉素诱导的毛细胞死亡。因此，PFT是治疗药物诱导的耳毒性的潜在分子。此外，我们的数据表明，PFT显着保护耳蜗细胞，而不能保护前庭毛细胞免受低剂量庆大霉素的影响。低剂量庆大霉素的内胰蛋白酶内注射可损害前庭毛细胞，已广泛用于治疗梅尼尔氏病的头晕。然而，庆大霉素引起的因耳蜗损伤引起的听力损失是主要问题。在这种情况下，PFT具有巨大的潜在临床应用。在这个项目中，我们将研究PFT保护机制。此外，我们还将描绘上游和下游信号通路的p53，该途径将绘制具有特定目标的地图，以供将来针对顺铂和庆大霉素耳毒性进行保护。我们将使用出生后大鼠的皮质器官的器官培养物，这是研究耳毒性的良好模型。该研究的结果将在开发新疗法以防止药物引起的耳毒性方面具有临床应用，并将有助于理解药物诱导的耳毒性的分子机制。