Three critical findings have been made over the last several years with important implications to the treatment of the deafened auditory system. First, there are significant changes to the peripheral auditory system as a consequence of deafness in the adult animal. Second, these changes impact on the reintroduction of input after deafness. Third, it is now possible to intervene and influence deafness-related changes to permit optimal processing of re-introduced input. Such interventions can be termed """"""""Tissue Engineering"""""""" and their basis development, and application drive our proposed studies. A great deal of our current knowledge regarding interventions that may effect the survival and function of the sensory nerves derives from in vitro studies of cells in culture and organotypic preparations. The goal of this investigation is to verify the validity of these interventions in vivo, and to test the efficacy and safety of potential interventions to """"""""engineer"""""""" the tissues of the inner ear in vivo. Our first specific aim is to test the utility and synergy of chemical and activity factors involved in the survival of the auditory nerve for enhanced spiral ganglion survival after deafness. We hypothesize that there are naturally multiple factors involved in the maintenance of spiral ganglion cells, which not only provides redundancy (for increased protection) but also synergy in effect, and we can achieve maximal enhancement with multiple factors. Our second set of studies how neurotrophic factors and stimulation induced activity can not only enhance spiral ganglion cell survival but also induce regrowth of auditory nerve peripheral process, which regress after inner hair cell loss. Our ultimate goal is to develop the knowledge base and the tools to intervene in and influence the deafened auditory system to provide the best possible environment for re-introduction of auditory information. Hopefully, these in vivo studies will provide a critical step in the transfer of this technology to human application. The interventions that are developed will provide the substrate essential for reconnecting regenerated hair cells in the future. The should directly enhance the benefit of cochlear prostheses at present.

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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Donahue, Amy
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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
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
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
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
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

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