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.

抽象的 顺铂是最广泛使用的抗癌药物之一，然而高达 70% 的患者可能患有严重的癌症 剂量限制性耳毒性。铂介导的听力损失不利于儿童的早期言语发育 儿童，可能会妨碍神经认知能力、社会融合和财务状况。因此，长期 与该提案相关的长期目标是评估膜转运蛋白在调节损伤中的作用 顺铂或其代谢物积累后对耳蜗细胞的影响。本提案的总体目标 旨在描述单羧酸转运蛋白 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 N-乙酰半胱氨酸 S-缀合物代谢物的摄取 顺铂 (NAC-1) 会导致耳蜗毛细胞严重受损并导致听力丧失。这样做的理由 该项目的目的是预测 MCT6 (rs4788863) 的功能性遗传变异体先前与相关 顺铂引起的耳毒性发生率较低。评估 MCT6 的作用机制 顺铂介导的听力损失对于解决该转运蛋白是否具有药物抑制作用是必要的 可以保护当前没有治疗或预防措施的不良事件。中央 将通过追求两个具体目标来检验假设：1）研究MCT6转运NAC-1的能力； 2)确定MCT6缺陷对顺铂诱导的体内耳毒性的保护作用。在第一个下 目的，MCT6高表达的体外模型将用于测量该转运蛋白的能力 调节 NAC-1 和顺铂的摄取。此外，rs478863 遗传变异的影响，或 将评估 MCT6 对铂摄取或细胞毒性的药理学抑制作用。在第二个目标下， MCT6 缺陷体内小鼠模型将用于评估顺铂引起的听力损失的严重程度 MCT6 转运蛋白的缺失。此外，我们将测量MCT6-中顺铂的药代动力学变化 缺乏的老鼠。这将为 MCT6 在顺铂或其衍生物的处理中的作用提供机制上的见解。 代谢物。本申请中提出的研究具有创新性，因为它代表了实质性的 通过评估MCT6作为耳蜗损伤调节剂的作用，偏离现状，通过促进 有毒顺铂代谢物的积累。拟议的研究意义重大，因为预计 确定 MCT6 是一种转运蛋白，可以通过药理学靶向来减轻或预防以下疾病的严重程度： 与癌症治疗相关的顺铂引起的听力损失。最终，预计此类知识将减少 将经历重大社会和经济挑战的患者数量，包括年轻人 小儿癌症幸存者。