Grant: Doctoral Research Award: Canada Graduate Scholarships

Cisplatin, which is a drug that is used to treat cancer, causes hearing loss (i.e., ototoxicity) in up to 80% of patients who receive this treatment. Some risk factors for this adverse drug reaction include younger age and higher drug dosage. Genetics also plays an important role in the development of cisplatin-induced ototoxicity (CIO). When cisplatin is given to patients, it can alter the amount of genes that are expressed in specific ear cells, with changes in DNA sequences (i.e., genetic variants) influencing these alterations. However, there is a knowledge gap regarding which genes, pathways and specific ear cells are affected. To overcome this, we will use cutting-edge technologies such as single-nuclei RNA-sequencing and single-nuclei ATAC-sequencing. These techniques will allow us to generate a map of how cisplatin changes gene expression in single nuclei that are present in mouse inner ears, using R packages, Seurat and Signac. (Objective 1). We will identify genetic variants that are associated with CIO in humans using data from previously published genome-wide association studies and determine if these variants are found in regions of the mouse genome that were changed by cisplatin (Objective 2). Genes whose expression is impacted by these cell-specific cisplatin-induced changes in the genome will be identified from the results of the joint snRNA-seq and snATAC-seq analyses. We will use the information from Objectives 1 and 2 to develop a genetic predictive model (i.e., polygenic risk score) to predict the risk of CIO (Objective 3). These objectives will allow us to identify specific genes, pathways, and cells that are associated with CIO, which will help us identify strategies that can predict and prevent CIO, such as identifying therapeutic targets to prevent CIO. Data generated from this research will also give us the opportunity to generate an open-source database where the biological functions of the genes that are involved in CIO can be explored.