Project 441861

Cisplatin is a chemotherapeutic which is used in the treatment of several cancers. Unfortunately, this cancer treatment also causes severe and debilitating adverse drug reactions such as hearing loss, which occurs in approximately 60% of children receiving this treatment. Once cisplatin is administered, it can change how much of a gene is expressed in specific tissues, the effects of which are mediated by genetic variants. These cisplatin-induced changes in gene expression are likely to result in adverse drug reactions in tissues where these changes are observed. However, no studies have examined the effect of cisplatin on gene expression in inner ear hair cells - the most important cells for hearing. This can be attributed to the difficulty in examining gene expression in these cells, which represent only approximately 3% of the cells found in the inner ear. Recent technological advances have allowed for the investigation of genes in single cells, providing the opportunity to examine gene expression patterns in the low abundance inner ear hair cells. My research aims to use these technologies to investigate the effect of cisplatin treatment on gene expression levels in inner ear samples obtained from mice. Using these data, in combination with data from genome-wide association studies of cisplatin-induced ototoxicity and publicly available gene expression databases, we will uncover small molecules that induce gene expression profiles that are highly dissimilar to the cisplatin-induced gene expression profiles. The potential of these small molecules to prevent hearing loss, without impacting the antitumor activity of cisplatin, will be investigated using mouse models.