Cellular responses to a traumatic insult include the activation of multiple pathways that lead either to survival (homeostatic pathways) or cell death (apoptotic or necrotic pathways). The control of these pathways requires the concerted efforts of second messengers, protein kinases, and transcription factors that will ultimately change the patterns of gene expression in the cell. Depending on the intensity of the stress, different genes will be activated, eventually shifting the balance from homeostatic pathways (at low stress) to cell death pathways (at high stress). This project intends to unravel some of these pathways and their contributions to noise-induced hearing loss. It is the underlying hypothesis - based on solid preliminary evidence - that an initial event in noise trauma is the formation of reactive oxygen species leading to the activation of transcription factors and upregulation of oxidant stress response genes. Specifically, the following aims will be addressed in a mouse model of noise-induced hearing loss: (1) the formation and distribution of reactive oxygen species and the activation of the transcription factors AP-1 and NF-kappaB; (2) the hypothesis that the phosphoinositide pathway (phosphoinositide-3-OH kinase; PI 3-kinase) and NF-kappaB integrate noise-induced signaling by mediating the effects of ROS and neurotrophic factor; (3) the expression of specific antioxidant genes and the localization of their protein products. The project is coordinated with the other projects and core facilities in this application both by the common theme and by shared coordinated design and shared animals. The joint analysis of the data will yield a wide-ranging and integrated model of cochlear stress responses which, in turn, will provide a rational basis for designing pharmacological interventions to prevent noise-induced hearing loss.
| Vicente-Torres, M Angeles; Schacht, Jochen (2006) A BAD link to mitochondrial cell death in the cochlea of mice with noise-induced hearing loss. J Neurosci Res 83:1564-72 |
| Matsunobu, T; Ogita, K; Schacht, J (2004) Modulation of activator protein 1/DNA binding activity by acoustic overstimulation in the guinea-pig cochlea. Neuroscience 123:1037-43 |
| Yamashita, Daisuke; Miller, Josef M; Jiang, Hong-Yan et al. (2004) AIF and EndoG in noise-induced hearing loss. Neuroreport 15:2719-22 |
