Repurposing momelotinib for the prevention of aminoglycoside-induced ototoxicity

重新利用莫洛替尼预防氨基糖苷类引起的耳毒性

• 批准号: 10341150
• 负责人: Jonathan Paul Fleegel
• 金额: $ 4.52万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341150
• 关键词: ACVR1 gene; Address; Adult; Adverse effects; Age; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Antibiotics; Area; Auditory; Auditory Brainstem Responses; Back; Bacterial Infections; Career Choice; Cells; Child; Clinic; Clinical; Cochlea; Communication; Communities; Cytoprotection; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Drug usage; Educational Curriculum; Ensure; Environment; Equilibrium; Evaluation; Exposure to; FDA approved; Feeling; Future; Global Change; Goals; Gram-Negative Bacterial Infections; Hair Cells; Health Benefit; Hearing; Hearing Tests; Hospitals; Human; Individual; Infection; Intervention; Janus kinase; Kanamycin; Label; Life; Mediating; Mental Depression; Methods; Mission; Mus; National Institute on Deafness and Other Communication Disorders; Neonatal Intensive Care Units; Otolaryngology; Outer Hair Cells; Pathogenesis; Patients; Pharmaceutical Preparations; Physicians; Prevention; Preventive treatment; Process; Property; Public Health; Publishing; RNA Sequences; Recording of previous events; Research; Research Project Grants; Research Training; Risk; Scientist; Sensory Hair; Sepsis; Septicemia; Strategic Planning; Students; Techniques; Technology; Therapeutic; Therapeutic Agents; Time; Toxic effect; Training; Tyrosine Kinase Receptor Inhibition; Universities; World Health Organization; Zebrafish; aminoglycoside-induced ototoxicity; base; cell injury; clinically relevant; combat; cost; drug candidate; drug repurposing; experience; experimental study; hair cell regeneration; hearing impairment; hearing restoration; improved; in silico; in vivo; inhibitor; knock-down; molecular drug target; mouse model; neonate; novel; otoacoustic emission; otoprotectant; ototoxicity; pre-clinical; preclinical study; prevent; prevent hearing loss; programs; protective effect; response; screening; side effect; single cell sequencing; systemic toxicity; therapy development; transcriptome

PROJECT SUMMARY: Aminoglycoside antibiotics are considered an essential group of medications by the World Health Organization. Each year, thousands of children and adults are prescribed aminoglycosides to treat severe gram-negative bacterial infections. This is especially prominent in the neonatal intensive care units, where over 80% of the neonates are prescribed aminoglycosides. Unfortunately, administration of aminoglycosides carries substantial risk for life altering side effects, namely irreversible hearing loss. This is especially evident in the fact that 15 out of every 100 neonates will experience hearing loss, as compared to the 1 to 3 out of every 1,000 babies who are born full term. Hearing loss alters an individual’s ability to communicate and is associated with feelings of isolation and depression. Substantial effort is still required to identify the first FDA approved therapeutic for prevention of aminoglycoside related ototoxicity. We are proposing this study with the long-term goal of providing a therapeutic to combat this ototoxic side effect. To date, we have collected promising preliminary data suggesting momelotinib, a drug currently with FDA fast track designation, could be repurposed for this use. In Aim 1, we will use an aminoglycoside treated sepsis mouse model to provide preclinical, functional hearing data on the ability of momelotinib to prevent aminoglycoside induced hearing loss. In our experiments proposed in Aim 2, we will utilize the well-established and translatable zebrafish model organism to identify the essential targets and mechanisms of hair cell protection by momelotinib. This project advances the mission of the NIDCD to promote interventions to treat communication and other disorders. Specifically, our mechanistic studies in Aim 2 address Priority Area 2 in Hearing and Balance Research to increase the understanding and pathogenesis of ototoxicity. In addition, our characterization of momelotinib as a promising preventative treatment for aminoglycoside induced hearing loss advances Priority Area 3, to improve the diagnosis, treatment, and prevention of hearing loss through the development therapies to resist cell damage. This project will be completed at Creighton University under the sponsorship of the well-established auditory scientist, Dr. Jian Zuo. Creighton University has a strong history of auditory research. It houses a Translational Hearing Center dedicated to research pursuits in the therapeutic prevention of hearing loss and hearing restoration through hair cell regeneration. The physician-scientist program at Creighton University provides a well-rounded, integrated curriculum and tailors educational and clinical experiences to each student and their career aspirations. Specifically, the gateway program and longitudinal clinic provide great opportunities for students to gain exposure to the field they are going to enter. There is also a clinical refresher course offered during the last year of research training, which will ease the transition of the students back into the clinic. Overall, the strong auditory research community, unique training environment and impactful research project, ensures that my time at Creighton University will facilitate my development to become an independent physician-scientist in the field of otolaryngology.

项目概要： 世界卫生组织认为氨基糖苷类抗生素是一组重要的药物。 每年，成千上万的儿童和成人服用氨基糖苷类药物来治疗严重的革兰氏阴性菌 细菌感染。这在新生儿重症监护病房尤为突出，新生儿重症监护病房超过 80% 新生儿服用氨基糖苷类药物。不幸的是，氨基糖苷类药物的给药会产生大量的副作用。 改变副作用的生命风险，即不可逆的听力损失。这一点在以下事实中尤为明显：15 每 100 名新生儿中就有 1 人会出现听力损失，而每 1,000 名婴儿中就有 1 至 3 人患有听力损失 足月出生。听力损失会改变个人的沟通能力，并与孤立感相关 和抑郁症。仍需要做出大量努力来确定第一个 FDA 批准的预防治疗方法 氨基糖苷类相关的耳毒性。我们提出这项研究的长期目标是提供一种治疗方法 以对抗这种耳毒性副作用。迄今为止，我们已经收集了有希望的初步数据表明 莫莫替尼（momelotinib）是一种目前获得 FDA 快速通道指定的药物，可以重新用于这种用途。在目标 1 中，我们 将使用氨基糖苷类治疗的脓毒症小鼠模型来提供临床前、功能性听力数据 莫莫替尼预防氨基糖甙类药物引起的听力损失的能力。在我们目标 2 中提出的实验中， 我们将利用成熟且可翻译的斑马鱼模型生物来确定基本目标和 莫莫替尼保护毛细胞的机制。该项目推进了 NIDCD 的使命，以促进 治疗沟通和其他障碍的干预措施。具体来说，我们在目标 2 中的机制研究解决了 听力和平衡研究的优先领域 2 旨在增加对耳毒性的理解和发病机制。 此外，我们将莫洛替尼描述为一种有前景的氨基糖苷类预防性治疗方法 诱发性听力损失推进优先领域 3，改善听力的诊断、治疗和预防 通过开发疗法来抵抗细胞损伤。该项目将在 Creighton 完成 大学由著名听觉科学家左健博士赞助。克赖顿大学 有着悠久的听觉研究历史。它设有一个致力于研究活动的翻译听力中心 通过毛细胞再生来治疗性预防听力损失和恢复听力。这 克赖顿大学的医师科学家项目提供全面、综合的课程和定制课程 每个学生的教育和临床经验及其职业抱负。具体来说，网关 项目和纵向诊所为学生提供了接触他们所在领域的绝佳机会 即将进入。在研究培训的最后一年还提供了临床进修课程， 将使学生轻松过渡到诊所。总体而言，强大的听觉研究社区， 独特的培训环境和有影响力的研究项目，确保我在克赖顿大学的时光 促进我发展成为耳鼻喉科领域的独立医师科学家。