In the last decade, we and others have demonstrated the improvement of spiral ganglion cell (SGC) survival and peripheral process regrowth post-deafening by exogenous neurotrophic factors or restoring electrical activity to neurons. Our proposed studies are directed at the further development of these """"""""tissue engineering"""""""" strategies with the goal of therapeutic intervention, creating the knowledge and technology to intervene and influence the deafened auditory system, providing the optimal environment to re-introduce auditory information. Using data collected in our laboratory and others, we have constructed a model of SGC pathophysiology post-deafening. The tenets of this model define our experimental aims - to assess the influence of treatment type on the degree of benefit achieved, characterize the interaction between multiple factors to increase treatment efficacy, evaluate promising embryological growth factors, and initiate a stem cell study to replace the auditory nerve. Our first specific aim (SA) tests the hypothesis that replacement of lost trophic support, via exogenous neurotrophin infusion or chronic stimulation, will be more efficacious in enhancing peripheral process outgrowth and electrical responsiveness than will antioxidants, whose primary action is through the arrest/inhibition of the apoptotic cascade. Our second SA is driven by the hypothesis that normal survival reflects the synergistic interaction of multiple factors that act at a number of levels in the cell survival pathways, and that multi-factor treatment will yield additive and synergistic effects. Our third SA assesses the hypothesis that during stress, mature auditory ceils regress biochemically, becoming responsive to factors most effective during development. For this aim we are fortunate to have access to a novel otocyst derived factor. In the fourth SA, we expand our vision of SGC treatments from """"""""protection"""""""" to """"""""replacement,"""""""" characterizing the efficacy of stem cell implants as a means to replace the auditory nerve. These in vivo studies will provide a critical step in the technology transfer to human application. The interventions that are developed will provide not only treatments that will directly improve cochlear implant function in the near future, but also, interventions to prevent nerve deafness in hearing ears, and the substrate essential for reconnecting regenerated hair cells to the central nervous system in the more distant future. ? ?

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-6 (01))
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Freeman, Nancy
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Fransson, Anette; Maruyama, Jun; Miller, Josef M et al. (2010) Post-treatment effects of local GDNF administration to the inner ears of deafened guinea pigs. J Neurotrauma 27:1745-51
Hu, Zhengqing; Ulfendahl, Mats; Prieskorn, Diane M et al. (2009) Functional evaluation of a cell replacement therapy in the inner ear. Otol Neurotol 30:551-8
Reyes, Jeannie H; O'Shea, K Sue; Wys, Noel L et al. (2008) Glutamatergic neuronal differentiation of mouse embryonic stem cells after transient expression of neurogenin 1 and treatment with BDNF and GDNF: in vitro and in vivo studies. J Neurosci 28:12622-31
Maruyama, Jun; Miller, Josef M; Ulfendahl, Mats (2008) Glial cell line-derived neurotrophic factor and antioxidants preserve the electrical responsiveness of the spiral ganglion neurons after experimentally induced deafness. Neurobiol Dis 29:14-21
Altschuler, Richard A; O'Shea, K Sue; Miller, Josef M (2008) Stem cell transplantation for auditory nerve replacement. Hear Res 242:110-6
Glueckert, Rudolf; Bitsche, Mario; Miller, Josef M et al. (2008) Deafferentation-associated changes in afferent and efferent processes in the guinea pig cochlea and afferent regeneration with chronic intrascalar brain-derived neurotrophic factor and acidic fibroblast growth factor. J Comp Neurol 507:1602-21
Le Prell, Colleen G; Yamashita, Daisuke; Minami, Shujiro B et al. (2007) Mechanisms of noise-induced hearing loss indicate multiple methods of prevention. Hear Res 226:22-43
Maruyama, Jun; Yamagata, Takahiko; Ulfendahl, Mats et al. (2007) Effects of antioxidants on auditory nerve function and survival in deafened guinea pigs. Neurobiol Dis 25:309-18
Miller, Josef M; Le Prell, Colleen G; Prieskorn, Diane M et al. (2007) Delayed neurotrophin treatment following deafness rescues spiral ganglion cells from death and promotes regrowth of auditory nerve peripheral processes: effects of brain-derived neurotrophic factor and fibroblast growth factor. J Neurosci Res 85:1959-69
Le Prell, Colleen G; Hughes, Larry F; Miller, Josef M (2007) Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma. Free Radic Biol Med 42:1454-63

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