Basic Mechanisms in Hearing Loss of Cochlear Origin

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DESCRIPTION (provided by applicant): Objectives: Sensorineural hearing loss (SNHL) is strongly associated with many aspects of military service including blast injury. The objectives of this proposal are to improve the prevention and treatment of SNHL in veterans. Research Design: To improve our understanding of cellular processes underlying hair cell (HC) damage and loss, the contributions of molecular isoforms within known HC damage and survival pathways will be evaluated by determining their expression, and by evaluating HC loss in gene knockout mice. To improve SNHL prevention, pharmaceutical agents that can protect cochlear HCs from damage will also be identified. To improve treatment for SNHL, transcription factors that enhance the ability of Atoh1 to induce the conversion of mammalian cochlear non-sensory cells into HCs will be identified. In addition, modifications to mechanisms of gene silencing will be studied to identify epigenetic limitations on the ability of nonsensory inner ear cells to adopt features of the HC phenotype. Methodology: Studies will be performed using in vitro cultures of inner ear sensory epithelia, and in vivo studies of noise damage to the cochlea. For identification of HC protectants and transcription factors, innovative high-throughput methods have been developed to permit rapid, but targeted, screening of pharmaceuticals and induced gene expression in mammalian cochlear epithelia. Progress over the past period of funding: Mechanisms of ototoxin entry into HCs have been identified; cellular patterns of reactive oxygen species accumulation into HCs have been determined and antioxidant treatments evaluated; two novel intracellular pathways of HC protection have been defined; three gene mutations that lead to deafness have been identified; a critical period of HC development in which transplantation is possible has been determined; two novel transcription factors that enhance the conversion of nonsensory cochlear cells into HCs have been identified, and epigenetic manipulation of the cochlear sensory epithelium to enhance gene expression induced by a viral vector has been performed. Clinical Relationship: The prevention and treatment of SNHL is of great importance to veterans and to 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.