Rationale: More than 300 million people worldwide suffer from noise-induced hearing loss. Blast exposure due to artillery gunfire or explosives makes members of the military service particularly susceptible to acoustic trauma. The effects of noise are rapid, with damage to the inner ear occurring within minutes after exposure. Unfortunately, despite the enormous impact of noise-induced hearing loss, the mechanism(s) by which noise induces damage to the inner ear is poorly understood. Moreover, no therapeutic interventions that may help to prevent or alleviate this condition currently exist. Published work and preliminary studies support the therapeutic potential of quinoline molecules to treat hearing loss due to drug toxicity or noise trauma. Because we can easily modify the chemical structure of quinolines, we can potentially improve their therapeutic effect by introducing small changes that can result in better efficacy of the compound while preserving its low toxicity. Moreover, quinolines have been approved by the U.S. Food and Drug Administration as compounds that can be used in the pharmaceutical and food industries to inhibit bacteria growth, which would expedite their developmental phase for use in the inner ear as repurposed compounds. The proposed research meets the intent of the announcement since it will uncover novel therapies against noise-induced trauma. Results from this initial work will help to accelerate the identification of therapeutic quinoline molecules aiming to restore auditory function in affected individuals.
Objective: Identification of quinoline derivatives that will promote inner ear recovery and repair after noise damage.
Specific Aims: (1) Test the therapeutic effect of quinoline derivatives against noise trauma. The quinoline derivatives will be synthetized or acquired through commercial sources and tested in a zebrafish model for acoustic trauma. This approach will allow the rapid identification of quinoline derivatives with potential therapeutic properties. We will be able to screen at least one hundred compounds during a two- to three-month period. Those compounds promoting cell recovery and/or repair will be tested in a more relevant model for noise-induced trauma. A maximum of five top quinoline derivatives will be tested in mice. In this case, mice will be exposed to different noise-damage intensities followed by a single dose of one of the quinoline derivatives. The function of the inner ear will be assessed over a period of three weeks, after which the animals will be sacrificed and the tissue collected for microscopy studies. Because the cells involved in auditory function in fish and mammals can respond similarly to drug toxicity, compounds that show repair and/or recovery in fish should have a similar effect in mice. Successful completion of this aim will help to move our research closer to clinical trials for the use of quinoline derivatives as a therapeutic treatment against noise trauma. (2) Identify the mechanism of action of the quinoline derivatives. The goal is to identify quinolines' target to, ultimately, improve their chemical structure for better potency and low toxicity. There is evidence suggesting that quinolines block early steps in the generation of free radicals. The top lead candidates will be tested in a zebrafish line that carries a fluorescent indicator for mechanisms leading to free radical formation. If quinolines block these cell damage mechanisms, we will expect to observe a reduction of the fluorescence in animals treated with the quinoline derivatives. As an alternative strategy, we will decrease the presence of specific factors known to be responsible for cell survival. If any of these factors are the target of the quinoline derivatives, we will not observe recovery or repair in those animals, even in the presence of quinolines. Finally, we will confirm whether the same mechanisms are regulated by quinoline derivatives in the mammalian auditory system. Mice will be exposed to noise and the distribution and activation state of these factors assessed in the inner ear. Successful completion of this aim will move our research toward optimizing quinoline derivatives, aiming to improve the specificity for their target while preserving their low toxicity.
Exposure to damaging noise is still the primary cause for military service-related hearing loss and tinnitus. Estimates by the American Academy of Audiology and the House Committee on Veterans Affairs predict that approximately 21% of U.S. Army Veterans and 60% of Soldiers will show significant hearing impairment. Unfortunately, there is no available treatment for these patients. The short-term impact of this proposal is the identification of potential candidates to treat noise-induced hearing loss in animal models. The top lead candidates showing promising therapeutic capabilities will be further characterized in future studies that will lead to future clinical trials. Thus, successful completion of this study will have a direct benefit on military individuals and the American public in general by providing a much-needed alternative to restore auditory function after exposure to different scenarios of noise trauma.
|Effective start/end date||1/1/19 → …|
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