Hearing loss is America’s leading disability, affecting millions of people of all ages. To develop preventative and restorative clinical approaches, it is crucial to understand how the hearing process works on the cellular and molecular level. Hearing is mediated by sensory hair cells, part of a highly specialized neuroepithelium in the inner ear. The goal of our lab is to unravel the mechanisms that mediate the development, function, and maintenance of hair cells.
Discovery of novel proteins involved in hearing and deafness
Our lab uses a combination of proteomics, protein biochemistry, cell biology and mouse genetics tools to discover novel components involved in the molecular process of hearing. In short, we 1) sequence proteins in the sensory hair cell using mass spectrometry, 2) compare the proteomics data with genetic data to identify possible deafness genes, 3) characterize the function of these proteins, and 4) use the CRISPR/Cas9 system to generate transgenic mouse models to evaluate the role of these putative deafness genes in vivo. Techniques used: Mass spectrometry, cell biology, protein biochemistry, generation of transgenic mouse models
How do ototoxic drugs kill hair cells, and how can we prevent it?
Aminoglycosides comprise a highly potent class of antibiotics, but their clinical use is limited due to nephrotoxicity and ototoxicity. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited, and methods for clinical intervention have yet to emerge. We have recently found that the regulation of protein homeostasis in hair cells is severely affected by aminoglycosides. Protein homeostasis is at the center of general cellular homeostasis, and its dysregulation can activate various stress pathways leading to cellular degeneration and death. We are currently exploring the involvement of novel stress pathways in aminoglycoside-induced hair cell degeneration, with special emphasis on the discovery of novel drugs to prevent hair cell degeneration by blocking stress pathways.
CRISPR-mediated Gene therapy
Gene therapy to repair deafness mutations is a highly relevant goal in deafness research. In a remarkably short time period, the CRISPR/Cas9 system has emerged as arguably the most efficient genome engineering tool to date. In preliminary studies, we have demonstrated the efficiency of the CRISPR system for modification of deafness genes in the mouse model and are pioneers in applying this technology to deafness research. The goal of this proposal is to engineer a novel, modified CRISPR system that allows packaging in an adeno-associated vector, which presently is the only system for in vivo delivery of genetic material into adult sensory hair cells. This tool will be used to repair deafness mutations in a mouse model.