Project Summary Noise-induced hearing loss (NIHL) caused by exposure to intense or repeated noise results in damage to the sensitive structures within the cochlea. NIHL has become one of the leading occupational and recreational hazards afflicting nearly 40 million Americans. NIHL is also a serious concern for our military, and overall results in a high economic burden due to worker compensation and veteran disability. Although many treatments have been proposed to mitigate NIHL with promising results in preclinical studies, there are still no FDA-approved treatments for NIHL. Mild therapeutic hypothermia (30-33 °C) has been extensively studied as a neuroprotective strategy against various types of neurological traumas because of its ability to mediate various injury responses to trauma including oxidative stress, apoptosis, and inflammation. We aim to assess the therapeutic benefit of localized therapeutic hypothermia in mitigation of cochlear injury following acoustic trauma in a rodent model. In this proposal, we seek to engineer a novel non-invasive device used to induce localized mild therapeutic hypothermia post-NIHL and assess long-term functional hearing and cochlear neural substrate preservation. Our preliminary results suggest that controlled and localized therapeutic hypothermia provided to the inner ear post-NIHL significantly lowers hearing threshold shifts in hypothermia-treated animals when compared to normothermic control animals. Furthermore, we observe reduced cochlear synaptopathology with therapeutic hypothermia. To determine protective mechanisms underlying hypothermia, we will identify molecular pathways and gene networks that are regulated by temperature post-NIHL. A detailed characterization of the pathways in a relevant rodent model will provide future opportunities to identify additional synergistic otoprotective targets. Based on preliminary results, our primary mechanistic emphases will be on caspase-dependent apoptotic pathways and inflammatory responses with activated macrophage recruitment and expression. In the long-term, we aim to address the limited therapeutic options for NIHL that may be extended to various otological traumas, including blast-induced hearing loss or surgically-induced hearing loss.