Aminoglycoside antibiotics are essential for treating life-threatening bacterial sepsis, yet induce acute nephrotoxicity and permanent deafness/balance disorders. These noxious side-effects affect as many as 120,000 individuals each year in the US, particularly infants and premature babies. The long-term goal of this research is to prevent the cochlear uptake of aminoglycosides and subsequent ototoxicity, thus preserving life-long auditory function. Aminoglycosides like gentamicin cross the cochlear blood-labyrinth barrier into the cochlear fluids and enter sensory hair cells, inducing toxicity and hearing loss. Our recent data suggest that systemically-delivered gentamicin is trafficked from the strial vasculature, across the stria vascularis, into endolymph prior to hair-cell uptake. We have identified a candidate aminoglycoside transporter. Pharmacological inhibition of this transporter reduces cochlear, strial and hair-cell uptake of gentamicin.
The specific aims of this project are: "First, to determine if other aminoglycosides are predominantly trafficked to cochlear hair cells via the stria vascularis and endolymph in vivo (Aim 1)." Second, to test whether inhibitors of aminoglycoside trafficking preserves auditory function by preventing hair cell toxicity, and maintain the bactericidal efficacy of aminoglycosides. We will also determine if deletion of the candidate aminoglycoside transporter ameliorates aminoglycoside ototoxicity (Aim 2). "And, third, investigate whether structural modification of aminoglycosides prevents cochlear trafficking, hair cell uptake and hair cell toxicity (Aim 3). Identifying the routes and molecular mechanisms of aminoglycoside trafficking across the BLB and into hair cells is crucial to develop new pharmacotherapeutic strategies that preserve auditory function during aminoglycoside therapy. Clinically-relevant inhibitors of aminoglycoside trafficking should not affect the bactericidal efficacy of aminoglycosides. Preventing cochlear trafficking and hair cell uptake of aminoglycosides will allow clinicians to use aminoglycosides more aggressively for treating life-threatening bacterial sepsis, specific agents of bioterrorism, and for prophylaxis in combat, severe burns and blast injuries.

Public Health Relevance

Understanding how aminoglycoside antibiotics are trafficked across the blood-labyrinth barrier and enter the inner ear fluids and hair cells is crucial to developing pharmacotherapeutic strategies to prevent aminoglycoside-induced ototoxicity. This proposed research will determine: (i) the predominant trafficking routes of several aminoglycosides, (ii) identify whether stress increases aminoglycoside uptake, (iii) if inhibitors of aminoglycoside trafficking can preserve auditory function, and (iv) whether structural modification of aminoglycosides prevents trafficking across the blood-labyrinth barrier and into hair cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004555-11
Application #
8601873
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2000-07-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
11
Fiscal Year
2014
Total Cost
$413,740
Indirect Cost
$126,223
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Jiang, Meiyan; Wang, Qi; Karasawa, Takatoshi et al. (2014) Sodium-glucose transporter-2 (SGLT2; SLC5A2) enhances cellular uptake of aminoglycosides. PLoS One 9:e108941
Zhang, Ru; Zhang, Yi-Bo; Dai, Chun-Fu et al. (2013) Temporal and spatial distribution of gentamicin in the peripheral vestibular system after transtympanic administration in guinea pigs. Hear Res 298:49-59
Quintanilla-Dieck, Lourdes; Larrain, Barbara; Trune, Dennis et al. (2013) Effect of systemic lipopolysaccharide-induced inflammation on cytokine levels in the murine cochlea: a pilot study. Otolaryngol Head Neck Surg 149:301-3
Wang, Tian; Yang, Yu-Qin; Karasawa, Takatoshi et al. (2013) Bumetanide hyperpolarizes madin-darby canine kidney cells and enhances cellular gentamicin uptake by elevating cytosolic Ca(2+) thus facilitating intermediate conductance Ca(2+)--activated potassium channels. Cell Biochem Biophys 65:381-98
Uribe, Phillip M; Sun, Huifang; Wang, Kevin et al. (2013) Aminoglycoside-induced hair cell death of inner ear organs causes functional deficits in adult zebrafish (Danio rerio). PLoS One 8:e58755
Karasawa, Takatoshi; Wang, Qi; David, Larry L et al. (2011) Calreticulin binds to gentamicin and reduces drug-induced ototoxicity. Toxicol Sci 124:378-87
Alharazneh, Abdelrahman; Luk, Lauren; Huth, Markus et al. (2011) Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS One 6:e22347
Steyger, Peter S (2009) Potentiation of Chemical Ototoxicity by Noise. Semin Hear 30:38-46
Li, Hongzhe; Steyger, Peter S (2009) Synergistic ototoxicity due to noise exposure and aminoglycoside antibiotics. Noise Health 11:26-32
Karasawa, Takatoshi; Wang, Qi; Fu, Yi et al. (2008) TRPV4 enhances the cellular uptake of aminoglycoside antibiotics. J Cell Sci 121:2871-9

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