Research Update: “The Role of KCNQ4 Channels in Progressive Hearing Loss.” Liping Nie, Ph.D., University of California, Davis

DFNA2 is a type of inherited nonsyndromic progressive hearing loss. Hearing loss in DFNA2 families starts from high frequencies in the twenties or thirties, progressively affecting the mid and low frequencies later in life. Genetic analyses have demonstrated that mutations in the KCNQ4 gene, encoding a voltage-gated potassium channel, are responsible for DFNA2. Liping Nie, Ph.D., and colleagues are interested in how the KCNQ4 mutations lead to hearing loss.
 
Currently, the research work in Dr. Nie’s laboratory focuses on exterminating of the physiological role of KCNQ4 channels and impact of mutations in this channel on the auditory function. They have identified four KCNQ4 variants along with a series of proteins that regulate the channel function. In addition, they have demonstrated that the KCNQ4 channel and its interacting partners are differentially expressed along the tonotopic axis of the cochlea, consistent with the progressive nature of hearing loss in DFNA2. There is no doubt that these studies will improve our understanding of the basic mechanism of hearing and hearing loss, facilitating early diagnosis, prevention and even treatment of hearing loss.

Research Update: “Determination of Redox State in Hair Cell Mitochondria.” Richard Hallworth, Ph.D., Creighton University, Omaha, Nebraska. 

Dr. Hallworth’s research focuses on the primary cause of sensorineural hearing loss, which is the death of irreplaceable cochlear hair cells.  Research has shown that cochlear hair cells die due to aging, noise trauma, and aminoglycoside poisoning and are not replaced.   This project is to test this hypothesis by measuring the metabolic state of hair cell mitochondria in living hair cells using a novel imaging procedure. There have been demonstrated differences in the metabolic status of outer hair cells over inner hair cells – essentially, outer hair cells are more dependent on aerobic metabolism.  This finding points to a reason for the selective vulnerability of outer hair cells over inner hair cells.

In separate experiments, the metabolic effects of aminoglycoside antibiotics were tested to see if they could be observed after intoxication. With the help of Peter Steyger, Ph.D., Oregon Health and Sciences University, Portland, OR, a fluorescent-labeled gentamicin (an antibiotic used to treat many types of bacterial infections) was applied to a cochlear preparation. Simultaneously, gentamicin uptake and hair cell metabolism were observed.  Clear increases were found in metabolic demand in outer hair cells but not in inner hair cells within minutes after the uptake.  This was a clear indication that the selective vulnerability of outer hair cells is related to their metabolism. 

Research Update: “Characterization of a de novo Protein Expressed in the Mammalian Cochlea.” Jing Zheng, Ph.D., Northwestern University, Evanston, Illinois

Sensory hair cells deep within the inner ear convert the mechanical force of sound waves into signals that travel along the auditory neurons to give rise to the sensation of hearing in the brain.

A microscopic formation called the mechano-electric transducer (MET) is located at the top of the sensory hair cells and is responsible for initiating the process that converts the energy of sound waves into neurological signals. A molecule called cadherin 23 (CDH23) is believed to be a major component of the MET.

Zheng and colleagues wanted to investigate the nature of CDH23 and discover if any other significant proteins are associated with it and what their function might be. They had already identified one protein related to the MET, called carcinoembryonic antigen-related cell-cell adhesion molecule (CEACAM), and are further investigating its interaction with CDH23 and how and where its gene is expressed in the inner ear.
Zheng discovered that the gene for CEACAM is expressed in outer hair cells but not inner hair cells.

Zheng and colleagues are now investigating when the gene for CEACAM is expressed in the inner ear during development.

CEACAM is labeled with a green fluorescent antibody. It lights up on outer hair cells but not inner hair cells. Actin filaments in hair bundles are labeled with red fluorescent marker. 

Research Update: “The Effects of Selective Hair Cell Damage on Temporal Envelope Coding in the Auditory Nerve.” Michael G. Heinz, Ph.D., Purdue University, West Lafayette, Indiana

This project involves the collection of auditory-nerve fiber responses to amplitude modulated sounds from chinchillas. Responses are to be compared between animals with normal hearing and animals with sensorineural hearing loss arising from either selective outer-hair-cell or inner-hair-cell damage. A fairly complete set of data has been collected from normal-hearing chinchillas and the researchers are now collecting data from animals with selective hair-cell damage for this pilot study.

Selective outer-hair-cell damage is induced through administration of kanamycin (an antibiotic used to treat infections) over a several-week period, whereas selective inner-hair-cell damage is induced with administration of carboplatin (a chemotherapy drug used against some forms of cancer). A major goal of this pilot study is to settle on dosage protocols in chinchillas for the configurations and degrees of hearing loss that are appropriate for studying the neural encoding of perceptually relevant sounds. Both kanamycin and carboplatin have been successfully administered to an initial set of chinchillas.

The neural data collected in this study will provide useful comparisons to data collected over the last year from chinchillas with noise-induced hearing loss, for which results are more difficult to interpret due to the typical mixed configuration of outer- and inner-hair-cell damage.  A thorough understanding of the effects of hair-cell damage on temporal coding will provide useful insight for understanding the difficulties people with sensorineural hearing loss have in real-world listening environments.  This insight will be useful for future development of hearing-aid strategies to overcome these difficulties.