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 #
5R01DC004555-17
Application #
9849596
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2000-07-01
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
17
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Steyger, Peter S; Cunningham, Lisa L; Esquivel, Carlos R et al. (2018) Editorial: Cellular Mechanisms of Ototoxicity. Front Cell Neurosci 12:75
Kros, Corné J; Steyger, Peter S (2018) Aminoglycoside- and Cisplatin-Induced Ototoxicity: Mechanisms and Otoprotective Strategies. Cold Spring Harb Perspect Med :
Kachelmeier, Allan; Shola, Tsering; Meier, William B et al. (2018) Simplified, automated methods for assessing pixel intensities of fluorescently-tagged drugs in cells. PLoS One 13:e0206628
Garinis, Angela C; Kemph, Alison; Tharpe, Anne Marie et al. (2018) Monitoring neonates for ototoxicity. Int J Audiol 57:S41-S48
Jiang, Meiyan; Taghizadeh, Farshid; Steyger, Peter S (2017) Potential Mechanisms Underlying Inflammation-Enhanced Aminoglycoside-Induced Cochleotoxicity. Front Cell Neurosci 11:362
Jiang, Meiyan; Karasawa, Takatoshi; Steyger, Peter S (2017) Aminoglycoside-Induced Cochleotoxicity: A Review. Front Cell Neurosci 11:308
Garinis, Angela C; Liao, Selena; Cross, Campbell P et al. (2017) Effect of gentamicin and levels of ambient sound on hearing screening outcomes in the neonatal intensive care unit: A pilot study. Int J Pediatr Otorhinolaryngol 97:42-50
Adler, Henry J; Anbuhl, Kelsey L; Atcherson, Samuel R et al. (2017) Community network for deaf scientists. Science 356:386-387
Garinis, Angela C; Cross, Campbell P; Srikanth, Priya et al. (2017) The cumulative effects of intravenous antibiotic treatments on hearing in patients with cystic fibrosis. J Cyst Fibros 16:401-409
Chu, Yu-Hsuan; Escobedo, Jorge O; Jiang, Meiyan et al. (2016) Rhodamine analogues for molecular ruler applications. Dyes Pigm 126:46-53

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