Our senses rely on transformation, from the touch of a hand, a scent in the air, the sight of a friend, the sound of a child each transformed into a neural code that the brain pulls together into perception. In our laboratory, we are interested in the molecular physiology that underlies the transformation of sound in the cochlea. For this, we focus our attention on a group of sensory cells, so called hair cells, and the nerves that innervate them. We approach the study of these excitable cells in three inter-related areas: (1) ion channel regulation, (2) development, and (3) trauma and regeneration. Our goal is to unravel the molecular events that govern ion channel function in the normal, developing, and abnormal ear.

Deafness primarily results from pathology in the cochlea, and within the cochlea, sensory hair cells appear particularly vulnerable to noise trauma and ototoxic drugs. These cells play a central role in converting sound into the neural code that ultimately leads to hearing. Sound waves trasmitted into the cochlear fluids excite a tuft of "hairs" protruding from the hair cell, altering the membrane's electrical potential and triggering neurotransmiter release onto the auditory nerve. The interplay of mechanotransduction current, calcium and potassium channels, and synaptic events govern how sound is encoded in the periphery. Our research addresses the fundamental biophysical processes in cochlear physiology.

One area of research is concerned with the function of ion channels. Here, our studies currently focus on two important potassium channels (BK and KCNQ4). Large-conductance, calcium-activated BK channels are largely responsible for the hair cell’s ability to synchronize, or phase-lock, to low frequency sounds. Moreover, gradients in the molecular structure and biophysical properties of BK channels along the cochlea underlie frequency tuning in the ears of many lower vertebrates. Our studies explore how distinct BK channel variants are generated and regulated in the mature, developing, and injured cochlea. We are also investigating how post-translational modification of BK channels may affect hair cell physiology (e.g. in response to nitric oxide, hormonal influence, phosphorylation pathways). In another project and in collaboration with Dr. Sally Camper (Human Genetics), we are exploring the connection between hypothyroid-mediated deafness and deficits in BK and KCNQ4 channel function.

A second area of research seeks to understand the mechanisms underlying the acquisition of ion channel currents around the onset of hearing. The sequential appearance of various currents appears important for establishing the frequency-coding maps in higher, central auditory regions. Moreover, delayed acquisition of various channels results in hair cell death, dysfuncitonal synaptogenesis, and deafness.

A third area of research explores the molecular events leading to noise and drug-induced cochlear pathology. A common pathway in both noise and ototoxic injury is oxidative stress. In one series of experiments, we hope to provide a link between lipid peroxidation and changes to lipid-protein interactions. Membrane-bound signalling complexes (e.g. synapses) are likely targets for free radicals produced by oxidative stress. These experiments will provide new insights into the molecular effects of noise and ototoxic drugs and point to new therapeutic interventions. In related experiments, we are collaborating with Dr. Yehoash Raphael (Kresge Hearing Research Institute), who has recently shown the ability to genetically induce new hair cells in the deafened ear using novel gene therapy techniques. We hope to characterize the electrical properties of these new hair cells, providing the insights necessary to improve the gene therapy approach to curing sensorineural deafness.

Find more publications by Dr.Keith Duncan