Browsing by Subject "noise-induced trauma"

Our hearing perception is based on the ability to discriminate mechanical sound waves and to amplify and transduce them into electrical stimuli.This function is based on the complex cellular organization of the cochlea, the hearing organ. The sensory epithelium in the organ of Corti spirals along the cochlear duct in a tonotopic arrangement: every sound frequency elicits the strongest response at allocation along this duct. Sound stimulus is detected by three rows of outer hair cells (OHCs) which amplify- and tone-discriminate the sound stimulus, and by one row of inner hair cells (IHCs), which transduce the mechanical stimulus into electric impulses. Basal regions of the cochlea detect high- frequency sounds and apical regions detect low- frequency sounds. The complexity and sensitivity of the cochlea is linked with its vulnerability to various traumas. Most kinds of damage to the mammalian hair cells is irreversible, because these cells are not capable of regeneration. Hearing impairment has many etiologies. Common to them is that damage is permanent and no pharmacotherapy is available. Hearing impairment is often a disabling condition and it has vast societal consequences. The number of hearing impaired people is constantly increasing and the WHO has estimated that 10% of the world`s population will suffer from disabling hearing loss in 2050. Mesencephalic astrocyte- derived neurotrophic factor (MANF) is an unconventional, ER-resident protein that promotes ER- homeostasis. It has been associated with cytoprotective functions in many neurodegenerative disease- models and shown to promote recovery after ischemic trauma. MANF expression has been previously found in many cell-types in the cochlea, including OHCs and IHCs. Its deficiency in a mouse model led to upregulation of ER-stress markers and a robust, tonotopic base –to apex gradient loss of outer hair cells and severe hearing loss. This study examines the role of MANF in noise-induced trauma in the hair cells of the cochlea. In a conditionally inactivated (Manf -/- cKO) mouse model in the C57BL/6J – background, where Manf has been inactivated from most of the cochlear cells, I studied, if Manf -deficiency sensitizes the cells to noise-induced cell death in two age-groups. I also examined the basic and noise- induced MANF expression, using two mouse- strains, C57BL/6J and CBA/Ca. I also examined OHC stereociliary bundle morphology to find out if noise induces morphological changes in Manf cKO-mice that differ from noise-exposed C57BL/6j wild type mice. This study found that OHCs have a low MANF- expression, whereas in IHCs the expression is strong. MANF is expressed in a base- to apex gradient in the OHCs of the two mouse-strains examined, in a uniform pattern, that correlates with vulnerability, implicating that low levels of MANF predispose basal OHCs to vulnerability. MANF expression in the IHCs was non-gradiental. Noise did not induce upregulation, as was expected, but instead noise induced downregulation of MANF in the basal region of the OHCs by an unknown mechanism in both mouse-strains.This suggests that noise-induced trauma induces ER dyshomeostasis, possibly independent of ER stress response pathways ,unfold protein response (UPR). This study also demonstrates that MANF deficiency sensitizes the OHCs to noise- induced trauma, resulting in more elevated OHC loss and hearing thresholds. This sensitization is mainly caused by a progressive degenerative changes seen in the OHC stereociliary bundles of Manf cKO-mice, and is associated with more severe noise-induced hearing loss. The results of my study suggest that MANF has an important, yet unknown, protective role in noise-induced trauma in OHCs. These results support the possible role of MANF as a therapeutic agent in a noise-induced trauma.