Sensory hair cells undergo programmed cell death PC following trauma to the inner ear. Our laboratory has identified some of the molecules involved in hair cell death and the proposed experiments will determine whether interfering in the PCD pathway promotes functional hair cell survival in vivo. Head movements relative to gravity produce co- activation of hair cells found in the otolith organs and semicircular canals. In response to such head movements, compensatory eye movements (e.g. vestibular-ocular response, VOR) are produced so that the visual scene does not slip across the retina and cause disorientation. Chickens treated the aminoglycoside streptomycin sulfate display severe balance disorders and a loss of VOR [7]. Caspases are cysteine proteases that mediate PCD. Upon activation, caspases target critical cellular proteins leading to PCD. Cell permeable peptides (e.g. zVAD) can inhibit caspases and prevent PCD in a variety of neurons. Although numerous studies have demonstrated that caspase inhibitors can promote neuronal survival in vitro, few studies have examined the effectiveness of caspases inhibitors in vivo. Other studies have shown that general caspase inhibitors (e.g. zVAD) can promote hair cell survival in the presence of aminoglycosides in vitro [2, 3]. It is not known, however, whether hair cells that are rescued by caspase inhibition can still function as sensory receptors. To test the efficacy of zVAD in vivo, we will quantify the chick's motion-evoked VOR in aminoglycoside-/zVAD- treated animals. We will also obtain anatomical data to correlate hair cell loss with the status of the VOR.
| Matsui, Jonathan I; Gale, Jonathan E; Warchol, Mark E (2004) Critical signaling events during the aminoglycoside-induced death of sensory hair cells in vitro. J Neurobiol 61:250-66 |
| Cunningham, Lisa L; Matsui, Jonathan I; Warchol, Mark E et al. (2004) Overexpression of Bcl-2 prevents neomycin-induced hair cell death and caspase-9 activation in the adult mouse utricle in vitro. J Neurobiol 60:89-100 |
| Matsui, Jonathan I; Haque, Asim; Huss, David et al. (2003) Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo. J Neurosci 23:6111-22 |
