Repurposing momelotinib for the prevention of aminoglycoside-induced ototoxicity

项目总结： 氨基糖苷类抗生素被世界卫生组织认为是一类基本的药物。 每年，数以千计的儿童和成人被开出氨基糖苷类药物来治疗严重的革兰氏阴性 细菌感染。这在新生儿重症监护病房尤为突出，那里80%以上的 给新生儿开的是氨基糖苷类药物。不幸的是，氨基糖苷类药物的使用 改变副作用的生命风险，即不可逆转的听力损失。这一点在以下事实中尤为明显：15人出局 每100名新生儿将经历听力损失，相比之下，每1000名婴儿中有1至3名 出生足月。听力损失会改变个人的沟通能力，并与孤立感有关 和抑郁症。仍需付出大量努力才能确定FDA批准的第一种预防糖尿病的治疗方法 氨基糖苷类药物相关性耳毒性。我们提出这项研究的长期目标是提供一种治疗方法 来对抗这种耳毒性副作用。到目前为止，我们已经收集了有希望的初步数据，表明 莫美洛替尼是一种目前获得FDA快速通道指定的药物，可能会被重新用于这一用途。在目标1中，我们 将使用氨基糖苷类药物治疗的脓毒症小鼠模型提供临床前、功能性听力数据 莫洛替尼预防氨基糖苷类听力损失的能力。在我们在目标2中提出的实验中， 我们将利用成熟和可翻译的斑马鱼模式生物来确定基本目标和 莫洛替尼保护毛细胞的机制。该项目推进了NIDCD的使命，促进 治疗沟通障碍和其他障碍的干预措施。具体地说，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，我们将莫美洛替尼作为氨基糖苷类药物的一种有希望的预防性治疗。 诱发听力损失推进了优先领域3，以改进听力的诊断、治疗和预防 通过发育疗法来抵抗细胞损伤的损失。该项目将在克雷顿完成 由著名的听觉科学家简佐博士赞助的大学。克雷顿大学 在听觉研究方面有着深厚的历史。它有一个致力于研究的翻译听证中心 在治疗预防听力损失和通过毛细胞再生恢复听力方面。这个 克雷顿大学的医生-科学家项目提供全面的、综合的课程和裁缝 为每个学生和他们的职业抱负提供教育和临床经验。具体地说，网关 计划和纵向诊所为学生提供了接触他们所在领域的极好机会 要进去了。在过去一年的研究培训期间，还有一个临床进修课程，它 将使学生重新回到诊所的过渡变得容易。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，确保了我在克雷顿大学的时间将 帮助我成长为耳鼻喉科领域的独立内科医生兼科学家。

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.