Steven Green, PhD, is a professor of biological sciences, otolaryngology at the University of Iowa in Iowa City, and the recipient of a 2005 American Hearing Research Foundation Derlacki Grant for his project, “Role of JNK Signaling in the Death of Spiral Ganglion Neurons After Hair Cell Loss.”
Dr. Green’s research focuses on how the death of hair cells in the cochlea causes the subsequent death of the spiral ganglion neurons (SGNs). In normal hearing, the hair cells within the cochlea vibrate in response to sound and convert the vibration into the electrical and chemical signals that are the language of the nervous system. These signals transmit and process sound information to the SGNs, which relay the information to the brain where it is interpreted as sound. Hair cell death is the major cause of deafness, especially congenital (inherited) deafness and hearing loss associated with aging. Cochlear implants electrically stimulate the SGNs directly, bypassing dead or damaged hair cells. However, in the absence of hair cells, SGNs may gradually degenerate and die as well. Dr. Green received a grant from the AHRF several years ago to investigate the relationship between hair cell death and SGN death. A long-term goal is to protect SGNs in cochlear implant users.
With his AHRF grant, Dr. Green and colleagues discovered that SGNs exhibit specific molecular changes when they die subsequent to loss of hair cells. A crucial change centered around a signaling molecule called Jun N-terminal Kinase, or JNK. In rats that were artificially deafened, SGNs gradually die but at any one time just a few of SGNs show signs of dying. In the SGNs that were dying, there were higher levels of activated JNK and JNK signaling. Now that Dr. Green realized that the activation of the JNK molecules and cell death were correlated, he wanted to find out if JNK signaling actually caused SGN death and if blocking JNK activity would rescue or prevent SGNs from dying. Finally, he wanted to know what prevented the activation of JNK in normal ears. Similar studies have also been initiated elsewhere investigating potential therapeutic roles for JNK inhibitors in neurodegenerative brain diseases.
Using commercially available JNK inhibitors – a peptide inhibitor named I-JIP and a compound named SP600125 – Dr. Green’s lab showed that blocking JNK activation or JNK activity reduced the death of SGNs in culture. In animal studies with artificially deafened rats, the application of these reagents directly to the cochlea also prevented the SGNs from dying.
This procedure involved drilling a tiny hole at the base of the cochlea through which the chemical was infused. This happens to be the exact same spot that is drilled in humans getting cochlear implants. Dr. Green says that during this procedure, an extra tube connected to a pump containing the JNK blocker could be added to to the implanted electrode array to prevent SGN death in these patients.
Dr. Green believes that JNK inhibitors may be useful in preventing SGN death in people who are deaf and awaiting cochlear implants. “The longer a person is deaf, the more extensive SGN death can be,” says Green. “By giving these patients a JNK inhibitor, we can preserve more of their spiral ganglion neurons for the cochlear implant.” It has long been known that a strong predictor of cochlear implant success is the time elapsed between hearing loss and implantation.
Dr. Green has applied for National Institutes of Health (NIH) funding to determine precisely when a JNK inhibitor would have to be given in order to best prevent SGN death. He also wants to know if the inhibitor would have to be applied continuously (instead of just one time) to get the best results. “I am pretty confident we will be awarded NIH funding for this in the near future,” Dr. Green says. “And with that, we can begin to apply our knowledge of JNK and spiral ganglion neuron death to improve the outcomes of cochlear implant in patients with hearing loss.”