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: 10554341
• 负责人: Jonathan Paul Fleegel
• 金额: $ 3.89万
• 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/10554341
• 关键词: ACVR1 gene; Address; Adult; Adverse effects; Age; Aminoglycoside Antibiotics; Aminoglycosides; Antibiotics; Area; Auditory; Auditory Brainstem Responses; Back; Bacterial Infections; Career Choice; Cells; Child; Clinic; Clinical; Cochlea; Communication; Communities; Cytoprotection; Data; Data Set; Dedications; Development; Diagnosis; Disease; Disease Progression; Drug usage; Education; 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; Marketing; 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; 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; model organism; 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.

项目摘要： 氨基糖苷抗生素被认为是世界卫生组织的必不可少的药物。 每年，有成千上万的儿童和成人处方氨基糖苷，以治疗严重的革兰氏阴性剂 细菌感染。这在新生儿重症监护病房中尤为突出，其中80％以上 新生儿被处方氨基糖苷。不幸的是，氨基糖苷的给药可实现 改变副作用的风险，即不可逆转的听力损失。这是15岁的事实，这是特别的证据 每100名新生儿中，每1000名婴儿中的1至3个婴儿中，每100名 出生的完整学期。听力损失改变了个人的交流能力，并与孤立感有关 和抑郁。仍然需要大量努力来识别第一个FDA批准的疗法以预防 氨基糖苷相关的耳毒性。我们提出了这项研究，其长期目标是提供治疗 打击这种耳毒性副作用。迄今为止，我们收集了有希望的初步数据 Momelotinib是目前使用FDA快速设计的药物，可以重新使用此用途。在AIM 1中，我们 将使用经过氨基糖苷处理的败血症小鼠模型来提供有关临床前的功能性听力数据 Momellotinib预防氨基糖苷诱导听力损失的能力。在我们在AIM 2中提出的实验中， 我们将利用公认和翻译的斑马鱼模型有机体来确定基本目标和 Momellotinib的毛细胞保护机制。该项目推进了NIDCD促进的任务 治疗沟通和其他疾病的干预措施。具体而言，我们在AIM 2地址中的机械研究 听力和平衡研究中的优先区域2，以增加耳毒性的理解和发病机理。 此外，我们对Momellotinib的表征是氨基糖苷的预防治疗 诱导听力损失提高优先区域3，以改善诊断，治疗和预防听力 通过开发疗法的损失抵抗细胞损伤。该项目将在Creighton完成 在良好的听觉科学家Jian Zuo博士的赞助下，大学。克雷顿大学 具有悠久的听觉研究历史。它设有一个致力于研究追求的转化听力中心 在治疗性预防听力损失和通过毛细胞再生的恢复中。 克雷顿大学的物理科学家计划提供了全面的，集成的课程和裁缝 每个学生及其职业愿望的教育和临床经验。具体来说，网关 计划和纵向诊所为学生提供了很大的机会，可以接触他们的领域 要输入。在研究培训的最后一年中，还有一个临床复习课程，该课程 将简化学生回到诊所的过渡。总体而言，强大的听觉研究界， 独特的培训环境和有影响力的研究项目，可确保我在克雷顿大学的时间 促进我的发展成为耳鼻喉科领域的独立身体科学家。