Basic Mechanisms in Hearing Loss of Cochlear Origin

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Objectives: Sensorineural hearing loss (SNHL) is strongly associated with many aspects of military service including blast injury. The overall objectives of this proposal are to improve the prevention and treatment of SNHL in veterans. Research Design: During the previous period of funding, using medium-throughput screening of hair cells (HCs) from the mammalian cochlea, we identified a number of novel antioxidants and cell signaling inhibitors that are capable of protecting cochlear HCs from high-dose ototoxic damage. Some of these protectants provided better protection than several previously described oto- protectants. We now propose to evaluate the most effective of these compounds in vivo, using a single, invariant model of noise-induced hearing loss in animals, so that the interventions can be strictly compared. We will also evaluate known HC protectants to provide benchmarks. This will allow us to identify optimal compounds for further development as pharmacological interventions in humans. Methodology: Studies will be performed using in vivo studies of noise damage to the cochlea, with intracochlear delivery of HC protectants beginning immediately after exposure. We will use a well- established mouse model of noise damage, delivery of compounds to cochlear perilymph with osmotic minipumps, serial auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) audiometry, and morphological evaluation of cochlear HCs and afferent nerve endings. Progress over the past period of funding: During the past period of funding, we developed a medium-throughput method for screening libraries of potential oto-protectants using the mammalian organ of Corti, the only tissue containing the damage-sensitive mammalian outer HCs. We identified several antioxidants and several cell-signaling pathway inhibitors that were highly effective, and had not previously been evaluated for HC protection. Using an electroporation model of organ of Corti transfection, we also screened more than 200 transcription factors for the ability to enhance HC regeneration caused by ATOH1 expression in nonsensory cells, discovering several novel factors with this ability. We discovered that gene therapy with espin1 dramatically enhanced stereocilia formation on regenerating HCs. Finally, we discovered a novel protective HC pathway mediated by ATP receptors that reduce activity in HCs at high stimulus levels, protecting them from noise damage. These studies resulted in 20 peer-reviewed publications to date. Clinical Relationship: The prevention and treatment of SNHL is of great importance to veterans and the VA. The effects of SNHL on veterans' quality of life are substantial. SNHL and tinnitus also account for more disability compensation in the VA than any other disorder, and rehabilitation costs are high. The proposed research is targeted at developing new and improved therapies for prevention and treatment of this important health problem.