Aminoglycoside antibiotics, like gentamicin, are critical for treating life-threatening infections, yet dosing is limited by toxic side-effects thatlead to acute renal failure and permanent hearing loss in as many as 120,000 individuals each year in the US. The long-term goal is to protect the cochlear sensory hair cells from drug-induced ototoxicity, and maintain life-long hearing function. We recently demonstrated that experimental models of inflammation typically induced by bacterial infections treated by aminoglycosides potentiate the cochlear uptake of aminoglycosides and exacerbate aminoglycoside-induced ototoxicity. This proposal asks three specific questions: 1: Which markers of inflammation influence cochlear uptake of aminoglycosides? 2: Is inflammation-potentiated ototoxicity reduced in models with disrupted inflammatory signaling? 3: Do otoprotectants reduce inflammation-potentiated ototoxicity? Identifying the inflammatory signaling mechanisms that potentiate aminoglycoside-induced ototoxicity is crucial to better protect cochlear function during life-saving aminoglycoside pharmacotherapy for infectious disease. These data will allow clinicians to optimize individualized anti-infective and aminoglycoside therapy for treating life-threatening infections, while protecting life-long cochlear function in patients with cystic fibross, tuberculosis and sepsis.

Public Health Relevance

Disseminated infections are treated with aminoglycoside antibiotics as an empiric life-saving intervention; yet, infection-mediated inflammation potentiates cochlear uptake of aminoglycosides and exacerbates aminoglycoside-induced ototoxicity. Thus, the ototoxic, and nephrotoxic, side-effects of aminoglycosides are directly potentiated by the very infection under pharmacotherapy. This proposal tests hypotheses to (i) identify which inflammatory signaling cascades potentiate the cochlear uptake, and ototoxicity, of aminoglycosides, and (ii) determine if candidate otoprotectants effective in healthy preclinical models are equally effective in endotoxemic models of aminoglycoside-induced ototoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004555-15
Application #
9632796
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2000-07-01
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
15
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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