Outer hair cells and noise-induced hearing loss

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Title: Outer hair cells and noise-induced hearing loss PROJECT SUMMARY Hearing loss is one of the most common sensory defects affecting millions of people globally. Insults such as noise, age and ototoxic drugs induce stress in hearing organs that leads to cochlear damage including loss of both outer hair cells (OHCs) and inner hair cell (IHC) synapses. Our current hearing measurements are unable to reliably detect low level cochlear damage. Most importantly, it is impossible to identify cochlear stress before irreversible tissue damage and hearing loss have already occurred. Thus, there is thus an urgent need for developing an effective method for detecting early cochlear stress and damage. Mammalian hearing requires mechanical amplification of sound by OHCs to produce high sensitivity and sharp frequency selectivity. OHCs are also the most vulnerable components in the cochlea, and are extremely sensitive to and often damaged from different assaults that cause overloaded Ca2+ and reactive oxygen species (ROS) in OHCs. Thus, OHC’s proteins may be a good choice for uncovering biomarkers to detect early cochlear stress. OHCs carry a unique cytoplasmic calcium-binding protein, oncomodulin (Ocm), at an exceptionally high concentration. Recent data obtained from other peripheral systems suggest that Ocm can be secreted into extracellular space and promote peripheral neural regeneration. Based on the published information and our preliminary data, we propose to investigate whether Ocm could function as an intracellular stress-sensor for OHCs, an extracellular serological biomarker for cochlear stress, and a standby ‘neurotrophic factor’ stored in OHCs. To address our hypothesis, we will determine whether stressful stimuli triggers Ocm secretion in in vitro systems (Aim I). Then, we will measure secreted Ocm in the bloodstream at different times after assaults, along with hearing measurements and anatomic histological analyses of the cochlea and blood. We intend to determine a correlation between cochlear damage, hearing loss, and secreted Ocm in the bloodstream due to different stressful stimuli (Aim II). Finally, spiral ganglion neuron (SGN) primary cell cultures and Ocm transgenic mouse models will be used to test Ocm's ability to promote SGNs' neurite regeneration and survival (Aim III). Our project explores a novel function of OHCs unrelated to their commonly known role in amplification by targeting a critical molecule unique to hearing organs. Therefore, the obtained knowledge regarding Ocm as a standby stress indicator and protector may significantly change the current view of OHCs’ role in cochlear sustainability. Such a novel mechanism is critical for developing therapeutic strategies to detect, prevent, and treat hearing loss.