Repurposing momelotinib for the prevention of aminoglycoside-induced ototoxicity

项目概要： 氨基糖苷类抗生素被世界卫生组织认为是一组必不可少的药物。 每年，成千上万的儿童和成人被规定氨基糖苷类药物治疗严重的革兰氏阴性菌， 细菌感染这在新生儿重症监护室尤为突出，超过80%的新生儿在那里接受治疗。 给新生儿开氨基糖苷类。不幸的是，氨基糖苷类的施用携带大量的 改变生命的副作用风险，即不可逆的听力损失。这一点尤其明显， 每100名新生儿中就有1 - 3人会出现听力损失，相比之下，每1,000名婴儿中就有1 - 3人会出现听力损失。 足月出生。听力损失改变了一个人的沟通能力，并与孤立感有关 和抑郁症仍然需要大量的努力来确定第一个FDA批准的用于预防 氨基糖苷类相关耳毒性。我们提出这项研究的长期目标是提供一种治疗 来对抗耳毒性副作用到目前为止，我们已经收集了有希望的初步数据， momelotinib是目前FDA快速通道指定的药物，可以重新用于此用途。目标1： 将使用氨基糖苷类药物治疗的脓毒症小鼠模型，以提供临床前，功能性听力数据， momelotinib预防氨基糖苷类诱导的听力损失的能力。在我们的目标2中提出的实验中， 我们将利用成熟的和可翻译的斑马鱼模式生物来确定基本目标， momelotinib保护毛细胞的机制。该项目推进了NIDCD的使命， 治疗沟通障碍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，以增加对耳毒性的理解和发病机制。 此外，我们将momelotinib描述为一种有前景的氨基糖苷类预防性治疗， 诱发性听力损失推进优先领域3，以改善听力损失的诊断，治疗和预防 通过开发疗法来抵抗细胞损伤。该项目将在克雷顿完成 在著名的听觉科学家左健博士的赞助下，克雷顿大学 在听觉研究方面有着悠久的历史它设有一个翻译听力中心，致力于研究工作 通过毛细胞再生治疗性预防听力损失和听力恢复。的 克赖顿大学的医生科学家计划提供了一个全面的，综合的课程和裁缝 教育和临床经验，每个学生和他们的职业抱负。具体来说，网关 计划和纵向诊所为学生提供了很好的机会，让他们接触到他们所在的领域。 要进去了。在研究培训的最后一年，还提供了临床进修课程， 会让学生们更容易回到诊所总的来说，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，确保我在克雷顿大学的时间将 促进我的发展，成为一个独立的医生，科学家在耳鼻喉科领域。

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.