Role of MCT6 in mediating cisplatin-induced ototoxicity

MCT6 在介导顺铂诱导的耳毒性中的作用

• 批准号: 10646995
• 负责人: Jason A Sprowl
• 金额: $ 23.6万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646995
• 关键词: Acetylcysteine; Address; Adverse event; Antineoplastic Agents; Bilateral Hearing Loss; Candidate Disease Gene; Cell Death; Cell Line; Cells; Child Development; Cimetidine; Cisplatin; Cochlea; Communication impairment; Dose Limiting; Drug Kinetics; Economics; Frequencies; Genetic; Goals; Hair Cells; Hearing Tests; Impairment; In Vitro; Knowledge; Lead; Literature; MEL Gene; Measures; Mediating; Membrane Transport Proteins; Mission; Mus; Music; National Institute on Deafness and Other Communication Disorders; Neurocognitive; Organ of Corti; Patients; Pharmaceutical Preparations; Pharmacogenomics; Platinum; Positioning Attribute; Preventive measure; Process; Public Health; Quality of life; Reporting; Research; Role; Severities; Speech; Speech Development; Testing; Treatment outcome; Work; cancer therapy; childhood cancer survivor; cisplatin induced hearing loss; cytotoxic; cytotoxicity; experience; genetic variant; genome wide association study; hearing impairment; improved; in vitro Model; in vivo; inhibitor; innovation; insight; interpatient variability; mouse model; novel; ototoxicity; overexpression; pharmacologic; prevent; prevent hearing loss; protective effect; social; social integration; therapeutic development; therapeutic target; therapy outcome; uptake

ABSTRACT Cisplatin is one of the most widely used anti-cancer drugs, however up to 70% of patients can suffer from severe dose-limiting ototoxicity. Platinum-mediated hearing loss is detrimental to the early speech development of children and can impede neurocognitive abilities, social integration, and financial status. Therefore, the long- term goal associated with this proposal is to assess the role of membrane transporters in regulating damage to cochlear cells following accumulation of cisplatin or its metabolites. The overall objective of this proposal is to delineate the involvement of the monocarboxylate transporter, MCT6, in mediating cisplatin-induced hearing loss. The central hypothesis is that MCT6 promotes uptake of an N-acetylcysteine S-conjugate metabolite of cisplatin (NAC-1) resulting in severe damage to cochlear hair cells and loss of hearing. The rationale for this project is that a predicted reduced functional genetic variant of MCT6 (rs4788863) was previously associated with lower rates of cisplatin-induced ototoxicity. Evaluating the mechanism by which MCT6 contributes to cisplatin-mediated hearing loss is necessary to address whether pharmacological inhibition of this transporter would be protective of an adverse event that has no current curative or preventative measures. The central hypothesis will be tested by pursuing two specific aims: 1) Investigate the ability of MCT6 to transport NAC-1; and 2) Determine the protective effect of MCT6-deficiency on cisplatin-induced ototoxicity in vivo. Under the first aim, in vitro models with high expression of MCT6 will be used to measure the ability of this transporter to modulate uptake of NAC-1 as well as cisplatin. Additionally, the influence of the rs478863 genetic variant, or pharmacological inhibition of MCT6, on platinum uptake or cytotoxicity will be assessed. Under the second aim, a MCT6-deficient in vivo mouse model will be used to evaluate the severity of cisplatin-induced hearing loss in the absence of the MCT6 transporter. Moreover, we will measure pharmacokinetic changes of cisplatin in MCT6- deficient mice. This will provide mechanistic insight into the role of MCT6 in the handling of cisplatin or its metabolites. The research proposed in this application is innovative because it represents a substantive departure from the status quo by evaluating the role MCT6 as a regulator of cochlear damage via facilitating accumulation of a toxic cisplatin metabolite. The proposed research is significant because it is expected to identify MCT6 as a transporter that can be pharmacologically targeted to reduce the severity of, or prevent, cisplatin-induced hearing loss associated with cancer therapy. Ultimately, such knowledge is predicted to reduce the number of patients who would experience significant social and economic challenges, including in young pediatric cancer survivors.

摘要 顺铂是使用最广泛的抗癌药物之一，然而高达70%的患者可以患有严重的 限量耳毒性。铂引起的听力损失不利于儿童早期言语发育 这会阻碍儿童的神经认知能力、社会融合和经济状况。因此，长久以来- 与这项提议相关的长期目标是评估膜转运蛋白在调节损伤中的作用 顺铂或其代谢物蓄积后对耳蜗细胞的影响。这项提案的总体目标是 目的是阐明单羧酸转运体MCT6在介导顺铂诱导的听力中的作用 损失。中心假设是MCT6促进摄取N-乙酰半胱氨酸S结合的代谢物 顺铂(NAC-1)导致耳蜗毛细胞严重损伤和听力丧失。这样做的理由是 项目是预测的MCT6功能减退的遗传变体(Rs4788863)先前被关联 顺铂耳毒性发生率较低。评估MCT6的作用机制 顺铂介导的听力损失是必要的，以解决药物对该转运体的抑制 对目前没有治疗或预防措施的不良事件起到保护作用。中环 假设将通过追求两个特定的目标来验证：1)研究MCT6运输NAC-1的能力； 2)体内检测MCT6缺乏对顺铂耳毒性的保护作用。在第一个下 目的：高表达MCT6的体外模型将被用来测量该转运蛋白的能力。 调节NAC-1和顺铂的摄取。此外，rs478863基因变异的影响，或 将评估MCT6对铂摄取或细胞毒性的药理抑制作用。在第二个目标下， 体内MCT6缺陷小鼠模型将被用来评估顺铂所致听力损失的严重程度。 MCT6运输机的缺席。此外，我们还将测定顺铂在MCT6中的药代动力学变化。 有缺陷的小鼠。这将提供对MCT6在处理顺铂或其 代谢物。本申请中提出的研究具有创新性，因为它代表了一项实质性的 背离现状，评估MCT6作为促进耳蜗术后损伤的调节器的作用 一种有毒的顺铂代谢物积聚。这项拟议的研究意义重大，因为预计它将 确定MCT6是一种转运蛋白，可以通过药物靶向来减轻或预防 与癌症治疗相关的顺铂引起的听力损失。最终，这样的知识预计会减少 将经历重大社会和经济挑战的患者数量，包括年轻患者 儿科癌症幸存者。