Noise-induced hearing loss (NIHL) is becoming increasingly common in industrialized countries, stemming from both workplace noise exposure and leisure activities. Corresponding with its functional deficit, loss of outer hair cells (OHCs) and synaptic ribbons are the primary inner ear pathology. Although a variety of biochemical and pathological events associated with OHC death have been reported, there is currently no established clinical therapy for the prevention or treatment of NIHL, owing largely to the lack of a comprehensive understanding of the precise molecular mechanisms and signaling pathways mediating OHC injury and loss of synaptic ribbons in response to noise exposure. The long-term goal of this research is to understand the molecular mechanisms that result in NIHL and to elucidate novel and rational pharmacological or molecular/genetic therapeutic interventions to ameliorate or prevent NIHL. We have previously reported that traumatic noise transiently depletes cellular energy reserves and increases levels of the energy sensor p- AMPK? in OHCs. Our exciting new preliminary results show an increased amount of mitochondrial calcium uniporter (MCU) and a decreased amount of the mitochondrial sodium calcium exchanger (NCLX) proteins in OHCs after noise exposure. The magnitude of these changes is positively correlated with noise intensity. Furthermore, such changes occur secondarily to noise-induced energy depletion and influx of calcium. Based on these data, the hypothesis is presented that the noise-induced increase of MCU moves calcium into mitochondria while the depression of NCLX reduces the extrusion of calcium out of mitochondria, actions that together create mitochondrial calcium overload. We will address this hypothesis using a comprehensive experimental approach employing both in-vivo studies with adult mice and a novel in-vitro model of energy depletion in an inner ear cell line model for testing specific aspects of the molecular mechanisms of NIHL. We also will use knockout mice, siRNA, gene therapy, and pharmacological compounds to block selected pathways that promote mitochondrial calcium overload in an attempt to achieve synergistic protection against NIHL. The results of this project will lead to new insights into mechanisms of NIHL and may direct the design of novel interventions for the prevention of NIHL benefiting the quality of life of individuals and reducing healthcare costs. In addition, the data generated in this proposal will make a significant contribution to our understanding of a broad range of inner ear disorders, since similarities have already been noted in the molecular events associated with noise-induced, drug-induced, and age-related hearing loss.
As one of the most frequent work-related disabilities in industrialized countries, noise-induced hearing loss has clear detrimental effects on the economy. Currently, there is no established clinical therapy for the prevention or treatment of noise-induced hearing loss, owing largely to the lack of comprehensive understanding of the precise molecular mechanisms and signaling pathways mediating sensory hair cell injury in response to noise exposure. The outcome of this proposal will lead to new insight into molecular mechanisms of noise-induced hearing loss and may direct the design of novel interventions for the prevention and treatment of noise-induced hearing loss benefiting the quality of life of individuals and reducing healthcare costs.
|Sha, Su-Hua; Schacht, Jochen (2017) Emerging therapeutic interventions against noise-induced hearing loss. Expert Opin Investig Drugs 26:85-96|
|Chen, Jun; Hill, Kayla; Sha, Su-Hua (2016) Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss. J Assoc Res Otolaryngol 17:289-302|
|Hill, Kayla; Yuan, Hu; Wang, Xianren et al. (2016) Noise-Induced Loss of Hair Cells and Cochlear Synaptopathy Are Mediated by the Activation of AMPK. J Neurosci 36:7497-510|
|Chen, Jun; Yuan, Hu; Talaska, Andra E et al. (2015) Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling. J Assoc Res Otolaryngol 16:347-56|
|Han, Yu; Wang, Xianren; Chen, Jun et al. (2015) Noise-induced cochlear F-actin depolymerization is mediated via ROCK2/p-ERM signaling. J Neurochem 133:617-28|
|Yuan, Hu; Wang, Xianren; Hill, Kayla et al. (2015) Autophagy attenuates noise-induced hearing loss by reducing oxidative stress. Antioxid Redox Signal 22:1308-24|
|Zheng, H-W; Chen, J; Sha, S-H (2014) Receptor-interacting protein kinases modulate noise-induced sensory hair cell death. Cell Death Dis 5:e1262|
|Oishi, Naoki; Chen, Fu-Quan; Zheng, Hong-Wei et al. (2013) Intra-tympanic delivery of short interfering RNA into the adult mouse cochlea. Hear Res 296:36-41|
|Oishi, Naoki; Chen, Jun; Zheng, Hong-Wei et al. (2013) Tumor necrosis factor-alpha-mutant mice exhibit high frequency hearing loss. J Assoc Res Otolaryngol 14:801-11|
|Chen, Fu-Quan; Zheng, Hong-Wei; Schacht, Jochen et al. (2013) Mitochondrial peroxiredoxin 3 regulates sensory cell survival in the cochlea. PLoS One 8:e61999|
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