An Update from 2010 Grant Recipient Nicole Schmitt, M.D. University of Washington, Seattle

Nicole Schmitt, M.D., Resident Physician in Otolaryngology, has been looking into the effects of a common chemotherapy drug called cisplatin, on hearing. Cisplatin has been given to treat head and neck cancers, lung, and other cancers for decades, however, one of its side effects is hearing loss, especially in the higher frequencies. Previous studies have shown a link between cisplatin and an inflammatory molecule naturally-occuring in the body called TNF-alpha. TNF-alpha is a molecule involved in the inflammatory response, and is activated when there is a wound, or other injury to the body. Cisplatin seems to activate TNF-alpha, which in the presence of cancer cells, is a postitive thing in that the reaction leads to the death of the cancer cell. But Schmitt hypothesizes that in the inner ear, cisplatin-induced TNF-alpha causes the death of hair cells and leads to hearing loss.

Schmitt will study the effect of cisplatin on TNF-alpha in both normal (or wild-type) mice, and in mice with the gene for producing TNF-alpha deleted (a TNF-alpha ‘knockout’ mouse model) and in mice engineered to over express TNF-alpha. Schmitt will administer a dose of cisplatin to these mice and then dissect out the inner ear. The degree of hearing loss and hair cell loss will be measured in each of these types of mice, to determine whether deficiency or excess of TNF-alpha changes the sensitivity of the inner ear to cisplatin.

Schmitt will also investigate changes in TNF-alpha levels in the inner ears of these mice following cisplatin treatment. Schmitt will use both immunohistochemistry- where the mouse TNF-alpha molecules will be linked to marker molecules that are a specific color, and will also measure the level of TNF-alpha being made in the inner ear using a molecular biology technique known as RT-PCR.

Schmitt hopes that a greater understanding of how cisplatin affects TNF-alpha will lead to a better chance of developing other drugs that may protect the inner ear from the cisplatin’s harmful effects while not interfering with its anti-cancer properties. Alternatively, Schmitt believes that these may be drugs delivered directly to the inner ear through the tympanic membrane to have a targeted protective effect.

Photomicrograph on the left represents the organ of Corti from a normal mouse. The inner and outer hair cells (IHCs/OHCs) are marked for the molecule myosin VIIa in red; the nerve fibers are marked for the molecule neurofilament in green; and cell nuclei are marked with a blue stain. Photomicrograph on the right represents the organ of Corti from a mouse treated with cisplatin. While the inner hair cells and nerve fibers are intact, many of the outer hair cells have died.