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.
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.
| 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; Sibrian-Vazquez, Martha; Escobedo, Jorge O et al. (2016) Systemic Delivery and Biodistribution of Cisplatin in Vivo. Mol Pharm 13:2677-82 |
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