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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结: