Since joining Feinberg’s faculty in 2002, Donna Whitlon, PhD, research associate professor of Otolaryngology – Head and Neck Surgery, has aimed to find new interventions to prevent and repair damage to spiral ganglion neurons in the cochlea, a cavity in the inner ear essential for hearing. Through her research, she works to uncover new mechanisms of spiral ganglion neurite elongation in hopes of informing drug discovery. Currently, there are no drugs specifically approved by the FDA to protect against or reverse hearing loss.
Whitlon’s work has been funded by the National Institutes of Health, American Hearing Research Foundation, Knowles Leadership Fund and is presently supported by two grants from the Office of Naval Research.
What are your research interests?
The anatomy of the cochlea, particularly the wiring of the local spiral ganglion neurons, captured my imagination over 30 years ago. I spent the early part of my career studying the anatomy, protein expression and development of the spiral ganglion nerve fibers. Now, in the Department of Otolaryngology, I am interested in a critical clinical question: How can we help to protect against or repair hearing loss? I would like to be able to intervene to protect damaged spiral ganglion neurons and encourage regeneration of their fibers and innervation. Overall, my laboratory aims to jumpstart drug discovery for hearing research using skills including biochemistry, cell biology and cell culture together with knowledge we have accumulated over the years about spiral ganglion development and morphology. We are now working toward identifying compounds that will stimulate neurites to regenerate their length in vitro, then advancing the most promising compounds to in depth evaluation in a hearing impaired animal model.
How does your research advance medical science and knowledge?
According to the National Institute on Deafness and Other Communication Disorders (NIDCD), disabling hearing loss increases with age until nearly 50 percent of those aged 75 and older are affected. The NIDCD also estimates that about 15 percent of Americans between the ages of 20 and 69 (about 26 million people) have high frequency hearing loss due to noise exposure. In the armed forces, exposure to high decibel noise (aircraft carriers, machinery, weapons fire) is virtually unavoidable, and, as a result, the Veteran’s Affairs reports that its major expenditures for service-related injuries are for problems related to hearing and balance. Personal protective devices and sound dampening engineering can only go so far, and we are left with a problem of hearing loss that has no solution other than hearing aids and cochlear implants, neither of which can return the user to normal hearing.
The spiral ganglion neurons in the cochlea are bipolar neurons that connect the primary auditory receptor cells, the hair cells, with corresponding cells in the cochlear nucleus. Because auditory information, such as frequency, intensity and timing, passes from the cochlea to the brain via these neurons, any interruption in their connections to the hair cells (neuron or hair cell death, loss of synapses, neuron or hair cell dysfunction) results in hearing loss.
High decibel noise, certain antibiotics, aging or toxic insults to the cochlea can cause damage to the spiral ganglion neurons and/or hair cells and cause hearing loss. Spiral ganglion neurons retract their peripheral fibers and eventually neurons can die. Spontaneous regrowth of the peripheral fibers is very limited, but the organized connections of the fibers connected to the brain can be generally retained. It is because of these connections that cochlear implants, whose action bypasses the synaptic connection between hair cells and neurons, can send hearing-related electrical information from the cochlea to the brain. Regeneration of the peripherally oriented fiber back to the hair cell region is one way to begin to reconnect neurons with surviving hair cells, or to improve the function of cochlear implants.
Because screening compounds for hearing loss in deaf animal models is prohibitive in time and resources, we focused on developing an in vitro screening approach that would allow us to narrow down a library of compounds to a few of the most promising that could be elevated to more in-depth analysis in deaf animal models. To do this, my lab developed the first dissociated primary cultures for mouse spiral ganglion, characterized it, quantified neurite growth under various conditions and miniaturized it for use in 384 well plates. We have used these cultures to carry out the first small molecule screen for spiral ganglion neurite elongation and found that inhibitors of the HMG-CoA reductase, the first step in the mevalonate pathway, stimulates neurite elongation by a non-cholesterol dependent branch of the pathway. We elevated the most promising inhibitor to evaluation in noise exposed guinea pigs and found that delivery of the drug directly to the cochlea before or at the time of noise exposure protected against noise induced hearing loss.
What types of collaborations are you engaged in across campus?
Auditory research has to be multidisciplinary. My key collaborator is Claus-Peter Richter, MD, PhD. He is a recognized expert on whole animal auditory experiments, including surgery, electrophysiology and cochlear imaging. Together we have been able to identify promising compounds by cell culture and biochemistry, then elevate them to in vivo analyses in deafened animals and image the soft tissue in whole cochleas with a novel technique using hard X-rays. Jing Zheng, PhD, has the expertise in molecular biology and Kazuaki Homma, PhD, contributes the expertise in patch clamp recordings for our neurons.
What resources at Northwestern have been helpful for your research?
We collaborate with the High Throughput Analysis Laboratory of Northwestern University for imaging our cultures and we consistently use the confocal microscopes in the Cell Imaging Facility to image immunolabeled cochleas from experimental guinea pigs. The Genomics Core has also been helpful. Importantly, Northwestern University is a well-known center for audiology and auditory research. Richter, Zheng, Homma and I with others in Feinberg and the Evanston campus are very fortunate to be fellows of the Knowles Hearing Center, a cross-campus, interdepartmental group dedicated to the prevention, diagnosis and treatment of hearing disorders. It is an active group that meets regularly, brings in well-known auditory seminar speakers and presents symposia on timely hearing topics.