ABSTRACT We previously demonstrated significant protection from cisplatin induced hearing loss using cool water ear canal irrigation. However, the study was limited to a single bolus injection of cisplatin and acute time period (Spankovich et al. 2016). More recently, we examined application of localized cooling of the ear canal with repeated doses of cisplatin, over an expanded period of time, and using an alternative method of cooling (ear bar cooled by a Peltier device). Here, we propose to advance our novel application of localized ear cooling in mitigation of drug induced hearing loss; which we call Cool OtOprotective ear Lumen (COOL) therapy. Hypotheses: We hypothesize that (1) our COOL therapy will show protection in a rat model; (2) protection from our COOL therapy is mediated by reduced cochlear uptake of cisplatin, expression or cold shock proteins, and reduced upstream and downstream cell apoptotic cell death pathways; (3) that we will observe protection from vestibular damage with our COOL therapy. Specific Aims: Aim 1. To determine whether COOL therapy reduces cisplatin uptake and auditory-vestibular pathology, increases the expression of transcripts that code for cold-shock proteins, and reduced cellular stress pathways. Study Design: For Aim 1, Guinea pig and Long Evans rats will be exposed to cisplatin while undergoing COOL therapy and compared to sham controls and warmed animals. Aim 1(a) will determine if our findings translate to another species (rat) and explore vestibular effects. Aim 1(b) will examine antibody immunostaining for cisplatin DNA-adducts, mass spectrometry measured platinum concentrations in cochlear tissue, and confocal images of animals treated with fluorescent tagged cisplatin. Aim 1(c,d) will examine expression of cold shock proteins and evidence of lipid perioxidation and caspase-3 activation.