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.
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.
|Chu, Yu-Hsuan; Escobedo, Jorge O; Jiang, Meiyan et al. (2016) Rhodamine analogues for molecular ruler applications. Dyes Pigm 126:46-53|
|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|
|Li, Hongzhe; Kachelmeier, Allan; Furness, David N et al. (2015) Local mechanisms for loud sound-enhanced aminoglycoside entry into outer hair cells. Front Cell Neurosci 9:130|
|Yang, Yuqin; Chen, Fangyi; Karasawa, Takatoshi et al. (2015) Diverse Kir expression contributes to distinct bimodal distribution of resting potentials and vasotone responses of arterioles. PLoS One 10:e0125266|
|Koo, Ja-Won; Quintanilla-Dieck, Lourdes; Jiang, Meiyan et al. (2015) Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Sci Transl Med 7:298ra118|
|Liu, Jianping; Kachelmeier, Allan; Dai, Chunfu et al. (2015) Uptake of fluorescent gentamicin by peripheral vestibular cells after systemic administration. PLoS One 10:e0120612|
|Cross, Campbell P; Liao, Selena; Urdang, Zachary D et al. (2015) Effect of sepsis and systemic inflammatory response syndrome on neonatal hearing screening outcomes following gentamicin exposure. Int J Pediatr Otorhinolaryngol 79:1915-9|
|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|
Showing the most recent 10 out of 35 publications