Hair Cell Responses to Ototoxic Drugs

? DESCRIPTION (provided by applicant): 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.